key: cord-0794741-0s6zbf5o
authors: Jafarzadeh, Abdollah; Chauhan, Prashant; Saha, Bhaskar; Jafarzadeh, Sara; Nemati, Maryam
title: Contribution of monocytes and macrophages to the local tissue inflammation and cytokine storm in COVID-19: Lessons from SARS and MERS, and potential therapeutic interventions
date: 2020-07-18
journal: Life Sci
DOI: 10.1016/j.lfs.2020.118102
sha: 1625a1889ac14d8482e0af531456beb3169861bc
doc_id: 794741
cord_uid: 0s6zbf5o
The COVID-19-, SARS- and MERS-related coronaviruses share many genomic and structural similarities. However, the SARS-CoV-2 is less pathogenic than SARS-CoV and MERS-CoV. Despite some differences in the cytokine patterns, it seems that the cytokine storm plays a crucial role in the pathogenesis of COVID-19-, SARS- and MERS. Monocytes and macrophages may be infected by SARS-CoV-2 through ACE2-dependent and ACE2-independent pathways. SARS-CoV-2 can effectively suppress the anti-viral IFN response in monocytes and macrophages. Since macrophages and dendritic cells (DCs) act as antigen presenting cells (APCs), the infection of these cells by SARS-CoV-2 impairs the adaptive immune responses against the virus. Upon infection, monocytes migrate to the tissues where they become infected resident macrophages, allowing viruses to spread through all organs and tissues. The SARS-CoV-2-infected monocytes and macrophages can produce large amounts of numerous types of pro-inflammatory cytokines and chemokines, which contribute to local tissue inflammation and a dangerous systemic inflammatory response called cytokine storm. Both local tissue inflammation and the cytokine storm play a fundamental role in the development COVID-19-related complications, such as acute respiratory distress syndrome (ARDS), which is a main cause of death in COVID-19 patients. Here, we describe the monocytes and macrophage responses during severe coronavirus infections, while highlighting potential therapeutic interventions to attenuate macrophage-related inflammatory reactions in possible approaches for COVID-19 treatment.
macrophages may contribute to the development of immuno-pathologic reactions [20, 22] .
The lung injury of SARS-CoV-infected patients appears to happen directly through viral disruption of alveolar and bronchial epithelial cells and macrophages, and indirectly via triggering inflammatory mediators [23] . Both infected-and uninfected-macrophages exist in large numbers in the lungs of severe SARS patients [24, 25] and are causally related to the severity of coronavirus infections. In this review, we discuss possible macrophage-mediated inflammatory responses in SARS-CoV-2 infection and propose potential therapeutic interventions for attenuating macrophage-related inflammatory reactions.
Macrophages express various types of pattern recognition receptors (PRRs). Therefore, they are able to identify viral-related pathogen-associated molecular pattern molecules (PAMPs) [26] . In mucosal pulmonary infections, alveolar macrophages and epithelial cells lining the airways, provide the initial sources of type I IFNs, while plasmacytoid DCs secrete type I IFNs when viruses pass the local barrier and become systemic [26] . The viral-related double-stranded RNA is a potent inducer of IFNs and macrophages serve as a major source of IFN-α and IFN-β in response to viral infections [27] . For RNA viruses such as coronavirus, task of clearing a widespread infection, thus exacerbating the disease pathology [33] .
Following the Th subset paradigm and based on the cultures of macrophages and in tumors, these cells are categorized into two principle subtypes, including M1 macrophages, which secrete great quantities of proinflammatory cytokines (such as IFN-γ, TNF-α, IL-6, and IL-12), nitric oxide and reactive oxygen species (ROS), whereas M2 macrophages release large concentrations of anti-inflammatory cytokines such as IL-10, TGF-β and IL-1 receptor antagonist [41, 42] . M2 macrophages may be more subcategorized to M2a, M2b and M2c types which are induced from non-polarized macrophages via stimulation with IL-4/IL-13, immune complexes plus TLR agonists, and IL-10/TGF-β/glucocorticoids, respectively [43] .
The M2d type (mentioned only in mice) can be induced from M1 macrophage via stimulation with adenosine [43] . The microenvironment of tissues under pathological and physiological circumstances can also influence the activity of the macrophages. Instead of a separate bipolar M1/M2 model, a vast range of macrophage activation states has been proposed to exist in resident tissues [44, 45] . Therefore, as the monocytes migrate to different tissues and differentiate to macrophages under the local environmental factors, macrophages can widely vary in their phenotypic and functional characteristics. For example, certain lung M1-Journal Pre-proof and M2-like phenotypes with differential markers were identified in patients and healthy individuals [46] .
According to experimental investigations using animal models of respiratory syncytial virus (RSV) infection, it has been proposed that the lung macrophage polarization toward an M1-like phenotype contributes to the control of viral replication [44] . In several viral respiratory diseases such as SARS and influenza, the virus infection causes significant depletion of macrophages (mainly M1-like phenotypes) via apoptosis and necrosis that facilitate the viral replication [44] .
However, the balanced activation of M2-like phenotype is essential to limit the RSV-mediated immunopathologic reactions [44, 47] . Liao et al. indicated that the bronchoalveolar lavage fluid (BALF) from patients with severe COVID-19 infection contained higher frequencies of FCN1 + -and FCN1 lo SPP1 + macrophages (M1-like macrophages), while BALF from patients with moderate infection and healthy controls contained a higher frequency of FABP4 + macrophages (M2-like macrophages) [46] .
In addition to inducing the antiviral response, type I IFNs can control the macrophage polarization [44] . Type I IFNs may cause M1-like type polarization through STAT-1 and STAT-2-related signalling pathways, while they can lead to M2-like macrophage polarization via STAT-3 and STAT-6-related pathways [44, 45] . Accordingly, in the presence of type I IFNs, the high expression of STAT-1 and STAT-2 in macrophages leads to their polarization toward M1-like type, while the high expression of STAT-3 and STAT-6 in macrophages causes their polarization toward M2-like type [44, 45] . Using an animal model of PRRSV infection, it was reported that STAT1-6 genes are expressed in alveolar macrophages, however, the gene expression of STAT1 and STAT2 was significantly increased (10-200 folds) compared to other STATs after virus infection [44] . It has been proposed that macrophages express differently various ratios of STAT molecules according to their tissue microenvironment and functional status, and IFNs perform a dual role in M1-and M2-like macrophage polarization [44] . However, macrophage-tropic viruses have been equipped with mechanisms to divert macrophage polarization in their favourite direction. For example, HIV can divert macrophage polarization toward M2-like type through the induction of IL-4 and IL-10 production [44] . Several types of DNA viruses induce M2-like macrophage polarization through encoding analogue IL-10 (vIL-10) [48] .
Depending on the virus type, the polarization of macrophages toward M2-like type may contribute to the viral infection persistence through dampening effective antivirus immune responses [44] . Moreover, the overproduction of the proinflammatory cytokines or cytokine storm may covert macrophages into an overinflamed phenotype that can contribute to pathologic reactions [44] . The involvement of multiple factors and their downstream transcription factors in macrophage differentiation suggest that the macrophage subsets strict polarization into M1-type and M2-type is unlikely and that such rigidity would run against the principle of cellular plasticity to optimize the need-based regulation of biological responses. The kinetics of the macrophage polarization during the various stages of COVID-19, its association with pathogenesis and its orientation in the favourite direction need to be evaluated in future studies.
A subgroup of peripheral CD14 + monocytes and macrophages separated from healthy individuals express ACE2 [49] that is used by SARS-CoV to infect these cells despite low or no replication [50] . SARS-CoV also enters into ACE2 nonexpressor leukocytes [51, 52]. The C-type lectin receptors-liver/lymph nodespecific intercellular adhesion molecule-3-grabbing integrin (L-SIGN) or DCspecific intercellular adhesion molecule 3-grabbing non-integrin (DC-SIGN) and antibody-mediated internalization can provide further routes for cellular infection by SARS-CoV [53, 54] . HCoV-229E effectively infects and kills DCs leading to a delay in the induction of adaptive anti-viral immune response, providing time for viral replicate in the host [55] . and macrophages [60] . Other receptors such as CD147 may mediate the entry of SARS-CoV-2 into T cells [61] , however, the CD147 expression by monocytes and macrophages from COVID-19 needs validation.
It should be mentioned that monocytes may have some limitations to support viral dissemination, such as short lifespan and inability to establish viral replication. The capability of SARS-CoV-2 to overcome these limitations, perhaps through enhancing the monocyte survival and differentiation of infected monocytes into productive long-lived macrophages, needs to be clarified in future studies. After the differentiation of the infected monocytes to tissue macrophages, viral replication can then begin, causing progeny virions that can infect the surrounding cells. Although, the SARS-CoV-2 persistence in the monocytes may be short-term without detectable viral replication, the SARS-CoV-2-infected monocytes can produce large amounts of inflammatory mediators that support COVID-19associated complications.
Antiviral neutralizing antibodies play a key role in viral clearance, but the antibody-dependent enhancement (ADE) happens when anti-viral antibodies fail to neutralize the virus [62, 63] . ADE facilitates viral internalization and enhances target cell infection by binding of virus-antibody complex to FcR [62] . Both neutralizing-and non-neutralizing antibodies may trigger ADE [64] . ADE has been J o u r n a l P r e -p r o o f [62] . In some coronavirus-related infectious diseases, passive transfer of antibodies or prior immunity, increase the disease severity [65] .
In the presence of vaccine-induced antiviral antibodies, SARS-CoV shows a higher tendency toward primary human leukocytes, which do not express the typical receptor for the virus. Anti-coronavirus antibodies can increase viral replication in macrophage cultures [66] . The anti-S antibody promotes the SARS-CoV infection of monocytic and lymphoid immune cell lines and human macrophages [67] . After the initiation of viral gene transcription and viral protein synthesis, the replication process is halted without the generation of the progeny virus [68] . ADE via FcγRIIA (CD32A) was more prominent than with FcγRIIB, as these receptors have an immunoreceptor tyrosine-based activation motif (ITAM) and immunoreceptor tyrosine-based inhibitory motif (ITIM), respectively [68] . As alveolar macrophages express high levels of FcγRIIA, the FcγRIIA-mediated ADE may play a key role in the COVID-19 pathogenesis [64] . The FcγRIIA is expressed by alveolar macrophages and once is ligated by IgG molecules, it signals through ITAM inducing pro-inflammatory cytokines such as IFN-γ, TNF-α, IL-1, and IL-6 [64] prompting the use of tocilizumab (an IL-6 receptor antagonist) in COVID-19related clinical trials [64] . The targeting of the FcγRIIA-related downstream signaling elements such as the Src family of tyrosine kinases may also attenuate the inflammatory responses [64] .
Primary inflammatory responses to SARS-CoV occur prior to the appearance of anti-virus antibodies and are mediated by viral replication, viral-mediated ACE2 downregulation, host anti-viral inflammatory responses and cellular death through apoptosis and/or pyroptosis [69] . Secondary inflammatory responses develop after the generation of anti-virus antibodies limiting viral replication. However, the binding of the virus-Ab complex to FcR can lead to the accumulation of proinflammatory M1 macrophages in the lungs escalating lung injury through secretion of inflammatory chemokines MCP-1 and IL-8 [69] . The binding of the virus-anti-S-IgG complex to FcR present on monocytes/macrophages induces proinflammatory responses and therefore, FcR blockade reduces the production of inflammatory cytokines [70] .
In Chinese macaques vaccinated with SARS-CoV-derived S protein, the acute lung injury was more severe than in unvaccinated control animals [70] . In SARS-CoV infected macaques, the development of anti-S IgG prior to viral clearance promotes the MCP-1 and IL-8 production in the lungs and enhances the recruitment of proinflammatory alveolar macrophages, and abrogates the wound-healing responses that result in serious lung injury [69, 70] . The adoptive transfer of the anti-S IgG to macaques reduces viral loads after subsequent challenge with SARS-CoV but caused significant alveolar damage than the control animals [70] . Similar observations concerning the SARS-CoV vaccine-induced lung damages have also been reported in mice and African green monkeys [71, 72] . The greater lung infiltration of eosinophils, and elevated levels of IL-5 and IL-13 have been also reported in MERS-CoV-vaccinated mice following challenge infection [73] .
The patients who died from SARS exhibited similar inflammatory responses, lack of wound healing-related macrophages, and quicker production of anti-virus antibody. Their sera increased the SARS-CoV-mediated IL-8 and MCP-1 secretion by human wound healing-related macrophages [70] . Indeed, in SARS-CoV infected patients, the development of ARDS accompanied with antiviral IgG seroconversion in 80% of patients [74] and the patients who developed the anti-S antibody faster had a higher chance of dying from the disease [75] . Collectively, the coronavirus-specific antibody may increase the uptake of viruses by macrophages through interaction with FcR, resulting in the activation of macrophages and the secretion of chemokines and other cytokines, which contribute to the immunopathogenesis and disease enhancement. 3), and CCL8 (MCP-2) in macrophages contributing to the pathogenesis of SARS [50, 76] . Furthermore, in non-productive infection of DCs, SARS-CoV induces the expression of CXCL10, CCL2, CCL3, CCL5, and TNF-α [50, 76] .
SARS-CoV-infected monocytes exhibit inflammatory responses and changes in the expression of immune-related genes [77] . Pro-inflammatory cytokines, including GM-CSF, IFN-α, IL-6, and TNF-α trigger the monocytes differentiation to macrophages [77] . Treatment of peripheral blood monocytes with S protein increases the expression of CXCL10, CXCL11, CCL15, CCL16 and CCL19. The expression of CCR5 (the receptor for CCL5, CCL4, CCL3), XCR1, Lymphotoxinβ receptor, IL-10RA and IL17R was also increased [77, 78] . The viral S proteintreated monocytes increase TLR2-activated NF-κB-mediated secretion of MIP-1β, IL-1β, IL-8, IL-6 and TNFα and attract neutrophils, monocytes, natural killer (NK)-, T-, and B cells to the infection site to instruct the initial adaptive immunity [78] . A truncated S protein induces the TNF-α and IL-6 expression in a murine macrophage cell line [79] . Higher blood levels of CXCL10 and CCL2-the chemotactic factor for monocytes/macrophages-have been detected in patients with SARS [33, 80] . These cells could be M2 macrophages promoting SARS-CoV-associated lung pathology [81] . The SARS-CoV-mediated chemokine production induces a cycle of monocyte/macrophage recruitment in a synergistic manner, that leads to the immunopathology [33]. Both CCL2 [82] and CXCL10 J o u r n a l P r e -p r o o f -21 -Jafarzadeh A. et al. [83] can suppress hematopoietic progenitor cell growth, which may contribute to lymphopenia, a prominent event in SARS [33] . Similarly, CCL2 and CXCL10 may contribute to the SARS-CoV-2-associated lymphopenia, that is observed in severe cases of COVID-19 [14] .
MERS-CoV-infected macrophages contribute significantly to the development of MERS symptoms [58] . MERS-CoV replication in the macrophages results in extreme cytotoxicity and induces the expression of pro-inflammatory mediators which may promote MERS-related complications [84] . MERS-CoV-infected macrophages secrete pro-inflammatory chemokines and cytokines such as IL-1β, IL-6 and CXCL8 [56] . MERS-CoV infection in MDMs and DCs leads to the release of IL-2, IL-3, CCL2, CCL3 and RANTES in humans [56] or CXCL10, CCL5, IL-12, and IFN-γ, although no IFN-β and low IFN-α levels were measured in mouse [85, 86] . MERS-CoV-infected human plasmacytoid DCs, produce large amounts of type I and III IFNs, in particular IFN-α, although the viral replication was abortive [87] . The expression of chemokines such as CXCL10, CCL2, CCL3, CCL5 and CXCL8 is also upregulated by abortively MERS-CoV-infected DCs and macrophages that may contribute to the influx of monocytes/macrophages into the infected tissues [86] causing tissue damage via promoting leukocyte aggregation in the lower parts of the respiratory tract [58] . The infiltration of macrophages and neutrophils in the lung tissues of the MERS-CoV-infected rhesus macaques [88] and the progression of pneumonia severity and respiratory dysfunction in MERS patients are attributed to the cytokine/chemokine induction [89] .
Excessive upregulation of the neutrophil-attractant chemokines (CXCL1, CXCL2, CXCL8, CXCL10, CCL2 and CCL7) and monocyte-attractant chemokines (such as CCL2, CCL3, CCL4, CCL7, CCL8, CCL20, CXCL6 and CXCL11) has been reported in BALF samples from COVID-19 patients [37] . These chemokines can perform a crucial role in the development of pulmonary dysfunction by recruiting leukocytes in the lungs [37] .In COVID-19, the infiltrated leukocytes in alveoli were mainly macrophages and monocytes [60] . There were also intermediate numbers of multinucleated giant cells with lower numbers of eosinophils, neutrophils and lymphocytes, [60] . The alveolar septum-related blood vessels were congested, edematous and widened, with a modest aggregation of monocytes and lymphocytes [60] . Liao et al. indicated that the severe and moderate COVID-19 patients had higher frequency of macrophages (M1-like macrophages) in BALF and higher CXCL9, CXCL10 and CXCL11 concentrations compared to healthy individuals. However, CXCL16 concentrations were greater in moderate patients than in severe infection [46] . Thus, lung macrophages in severe COVID-19
infection may play a more important role in promoting local inflammation by recruiting inflammatory cells. Macrophages can often crosstalk with the ACE2-expressing cells, in several organs such as the lung, liver and stomach. The CD74 is expressed on the macrophages and serves as a receptor for MIF (migration inhibitory factor), which participates in inflammatory responses [90] . SARS-CoV-2-infected cells can interact with macrophages in the lung, stomach and liver. Macrophages attracted by SARS-CoV-2-infected cells through CD74-MIF interaction and other pathways may play destructive or protective functions [90] . Therefore, the targeting of SARS-CoV-2induced chemokines in the monocytes, macrophages, and DCs may attenuate the inflammatory responses and prevent organ failure ( Figure 3B ).
Sudden and quickly advancing clinical exacerbation has frequently been reported in the late stages (about 7-10 days) of COVID-19 which is associated with the cytokine storm [37] . Despite some differences in cytokine patterns between patients with COVID-19, SARS and MERS, it seems that the cytokine storm plays a key role in the development of SARS-CoV-2-related complications such as ARDS [4, 6, 91] . Elevated circulating quantities of IL-1β, IL-2, IL-7, IL-9, IL-10, IL-17, G-CSF, GM-CSF, IFN-γ, TNF-α, CXCL8, CXCL10, MCP1, MIP1A and MIP1B have been detected in the COVID-19 patients, especially in those needing ICU facilities [92] . Many of these cytokines and chemokines from monocytes/macrophages can escalate the pathogenesis. In COVID-19 patients, the total number of monocytes/macrophages in peripheral blood may not vary between SARS-CoV-2-infected patients and healthy individuals, but there is a greater proportion of activated monocyte/macrophage in patients. The severely affected COVID-19 patients display a significantly higher proportion of larger monocytes [49] . These monocytes exhibit the CD14, CD11b, and CD16 expression, along with elements related with both M1 and M2 polarization, that secrete IL-6, IL-10, and TNF-α [49] . There is also a higher proportion of CD14 + CD16 + inflammatory monocytes in COVID-19 patients compared to healthy individuals [93, 94] . The proportion of CD14 + CD16 + monocytes is much higher in more serious pulmonary complications [49] . The proportion of GM-CSF and IL-6-producing monocytes is higher in severe patients, representing as association with cytokine storm [49] . The Th1 cell-derived GM-CSF can activate the monocyte/macrophage leading to the development of the IL-6-secreting CD14 + CD16 + monocytes, which may migrate to the lungs and induce subsequent lung damage along with the cytokine storm [49] .
lymphocytes [95] . In SARS-CoV infection, viroporin-3a activates the NLRP3 inflammasome and induces IL-1β secretion by macrophages, indicating the possible induction of pyroptosis [96] , which can cause the release of large amounts of pro-inflammatory factors.
ACE2 is a type I transmembrane protein, whose enzymatic domain placed on the outer surface of cells where angiotensin II is converted to angiotensin 1-7 [97] .
Angiotensin 1-7 is a vasodilator and acts as a modulator of the renin-angiotensin system (RAS) [97] . ACE2 reduces the angiotensin II levels, which have directly pro-inflammatory and pro-oxidant properties. ACE2 thus plays a pivotal role in the modulation of excessive inflammatory responses [97, 98] . ACE2 exerts beneficial effects in a number of pathological situations, including SARS-CoV-2 infection, as it directly protects the lungs against ARDS [99] . The ACE2-mediated virus internalization is facilitated by the host membrane cell TMPRSS2 protease, which primes the viral S protein to allow the virus to enter the cell [97, 99] . Virusmediated ACE2 downregulation can diminish its activity, attenuate its antiinflammatory properties, and reinforce the angiotensin II impacts in the susceptible patients [97] . Under inflammatory conditions, the transmembrane disintegrin ADAM17 can also cleave the membrane-linked ACE2, which releases ACE2 into circulation or interstitium [98, 100] .
ACE2 expression by monocytes/macrophages from COVID-19 patients is significantly lower than healthy individuals [49] . SARS-CoV S-protein downregulates ACE2 and induces the shedding of catalytically active ACE2 ectodomain [101] . SARS-CoV infection, as well as inflammatory cytokines such as IL-1β and TNF-α, can enhance ACE2 shedding [101] . The soluble ACE2 may be directly contributed to the inflammatory reactions of SARS-CoV, and perhaps SARS-CoV-2 [98] . The reduced activity of pulmonary ACE2 was related to the ALI/ARDS [98, 99] . The reduced ACE2 expression enhances vascular permeability, increases lung edema, increases neutrophil accumulation, and diminishes lung function [102] .
As mentioned above, monocyte-and macrophage-derived cytokines and chemokines can play a crucial role in the COVID-19 pathogenesis. Resident alveolar macrophages play a protective role during the early phase of SARS-CoV-2 infection [26] . However, large infiltration of monocytes, putative precursors of alveolar macrophages, may cause severe lung inflammation [24, 25] . Interfering with upstream signals causing cytokine production can effectively dampen the occurrence of the cytokine storm [103] . The TLR-and inflammasome-mediated signaling inhibitors can induce monocytes and macrophages to secrete proinflammatory mediators. The targeting of the TLR-related pathways (such as using IRAK inhibitors) and targeting the inflammasomes may have beneficial therapeutic impacts [104, 105] .
Interfering with cytokine-mediated signaling pathways could also significantly reduce hyperinflammation in patients with severe COVID-19. Inflammatory responses could be mitigated by targeting pro-inflammatory cytokines or their receptors. Several trials using IL-1 inhibitors, IL-6 inhibitors, TNF-α inhibitors and JAK inhibitors are ongoing [103] .
Interfering with massive monocyte infiltration can also attenuate local tissue inflammation. It seems that pathological macrophages mainly derive from circulating monocytes that massively infiltrate the lungs and other organs rather than from tissue-resident macrophage populations. The targeting of monocyte/macrophage-attracting chemokines using small-molecule antagonists, neutralizing monoclonal antibodies and siRNA can modulate the monocyte/macrophage recruitment to the inflamed organ and prevent tissue injury [106] . The circulating CD14 + monocytes accumulate in inflamed tissues using the chemokine receptor CCR2 [107] . CCR2 blockade could potentially help to reduce the accumulation of pathological monocytes in inflamed tissues, although other CCR2-independent mechanisms may also contribute to the monocyte accumulation in tissues during severe inflammation. Treatment with anti-CCL2 neutralizing antibodies may interfere with the recruitment of monocytes and subsequent macrophage accumulation. For example, in a murine model of hepatocellular carcinoma, it has been demonstrated that the blocking of the CCL2/CCR2 axis using a CCR2 antagonist inhibits the recruitment of inflammatory monocytes, infiltration of the tumor-associated macrophages (TAMs) and M2 macrophage polarization, which support anti-tumor immune response [108] . Trial targeting CCR5, another chemokine receptor that regulates monocyte and T cell migration, have been initiated in patients with COVID-19 (NCT04343651) [103] . The reprogramming of pro-inflammatory macrophages to anti-inflammatory macrophages may be also considered in COVID-19. For example, GM-CSF is known as an inducer of M1 macrophage polarization and the therapeutic agents inhibiting GM-CSF are in phase I and II clinical trials in patients with rheumatoid arthritis [109] .
Clinical trials using type I and type III IFNs have been initiated in COVID-19 patients to interfere with viral replication. The receptor of type III IFNs (IFN-λs) mainly expressed by epithelial cells and restricted types of leukocytes [110] . As receptor of type III IFNs has lower distribution compared to receptor of type I IFNs, thus IFN-λs can induce powerful local antiviral responses without triggering systemic harmful inflammatory responses. Therefore, the clinical use of IFN-λ in COVID-19 may be very promising, and clinical trials are undertaken (NCT04331899 and NCT04343976) [110] .
Although, IFNs may be protective during the early stages of the disease, the extended IFN-γ production could eventually cause macrophage hyperactivation.
Trials have been initiated using IFN-γ inhibitors in COVID-19 patients suffering from respiratory distress and hyperinflammation (NCT04324021) [103] .
Identification of the exact organ-specific macrophages-related markers can provide unique determinants for targeting different macrophage subsets in certain organs.
Novel drug delivery using nanoparticles could deliver therapeutic elements to tissue or specific macrophage subsets and exert manipulations with high specificity and low toxicity [111] . The monitoring of macrophage recruitment and responsiveness to drugs using noninvasive imaging methods like positron emission tomography is a great approach for promoting the delivery of drugs to macrophages [111] . Development of strategies to target infected monocytes and macrophages may also be considered. Mannosylated nanoparticles can selectively target macrophages via the mannose receptor (CD206) in vitro [112] . The beneficial effects of macrophage deletion using monoclonal antibody against M-CSF receptor have been also demonstrated in mouse models of colorectal adenocarcinoma and fibrosarcoma [113] . The safety, pharmacokinetics, pharmacodynamics, and anti-tumor activity of a human antibody against M-CSF receptor (AMG 820) in a human's phase I study of solid tumors was evaluated [114] . However, the singular treatment with AMG 820 exhibited weak antitumor activity. The manipulation of the macrophages using nanotechnology-based system exhibited promising beneficial effects in mouse models of tumors and inflammatory diseases [115] .
Melatonin may also have the potentials to limit the COVID-19-related complications due to its anti-inflammation, anti-oxidative and immune-promoting properties [116] . Melatonin suppresses NF-κB, inhibits the production of the proinflammatory cytokines, and exerts anti-inflammatory effects through inducing the sirtuin-1 which downregulates the macrophage polarization towards the proinflammatory form that may prevent ARDS development [116] .
A list of potential therapeutic agents with anti-viral, anti-bacterial, anti-parasitic, anti-proliferative-, anti-inflammatory-, immunosuppressive and immunomodulatory properties (experimental/repurposed) currently considered as potential candidates/employed for ongoing trials of COVID-19 management has been provided in Table 1 . The mechanism of action of the therapeutic agents has also been mentioned in Table 1 . Anti-viral agents have specific intervention points in crucial stages like viral entry, viral replication, translation of viral proteins, assembling of new virions and viral budding, etc. thereby they can suppress the multiplication of SARS-CoV-2 (Table 1 and Figure 3A ). Many therapeutic agents suggested for repurposing in the COVID-19 treatment are commercially available and their dosage, safety and toxicity in humans is well documented, due to years of clinical use. This can allow their rapid assessment in phase II-and III clinical trials [117] .
In mucosal respiratory infections, alveolar macrophages serve as the first anti-viral defense through production type I IFNs.
The induction of TLR2 (via S protein), TLR3, TLR7, TLR8 (via virus-derived RNA following internalization process) leads to the expression of the pro-inflammatory mediators and IFNs through induction of the transcription factors NF-κB, IRF3, and IRF7. Viral-derived RNAs activate PKR-and OAS-related anti-viral pathways. The cytoplasmic sensors such as MAD-5 and RIG-1 also recognize various types of virus-derived RNAs and signal through adaptor MAVS/ISP-1 (located on our membrane of mitochondria). SARS-CoV-2 affects the cells of the innate immune system in particular monocytes, macrophages, and dendritic cells. These cells of the innate system play a crucial role in curbing the viral replication through the induction of Type-I IFNs assisted with the complement proteins and natural immunoglobulins against viral epitopes. These cellular responses (induction of proinflammatory mediators and IFNs Type-I, III) are tightly regulated by a series of intracellular signaling pathways elicited by surface receptors like TLRs, DC-SIGN, FcRs, and ACE-2 and TMPRSS2. Upon the viral entry into the host cells (via the clathrin-dependent internalization or ACE-2 mediated internalization) the spontaneous unloading of viral RNA is a subsequent step that follows. The viral RNA triggers the activation of intracellular RNA sensors like RIG-1 and MDA-5 each operating with distinct RNA conformations. RNA sensors then interact with MAVS that initiates Type-1 IFN signaling by activating the nuclear translocation of NF-κB and IRF3. The oligomeric RIG-1-CARD assembly and the polymeric formation of MAVS act as a signalosome for conducting the viral sensing signals further, which bifurcates into the activation of TRAF-2/6 to activate IKK complex and NF-κB activation. The other branch signals through TRAF-3 and activates the TANK/IKKγ/IKKε/TBK1 complex that acts as activators of IRF-3/7. Altogether the IRF-3/7 activation along with NF-κB drives the IFN and proinflammatory gene expression with the help of CREB-binding protein/p300 and transcription factors c-Jun and ATF-2. The IFN synthesized and secreted this way acts on the distant cells (paracrine) mode for spreading anti-viral immunity and in autocrine modes to fortify the intracellular viral clearance. SARS-CoV-2, however, attenuates these signaling pathways at various interception nodes. SARS-CoV proteins like ORF-9b may attenuate this antiviral response through targeting of MAVS by seizing poly (C)binding protein 2 (PCBP2) and the HECT domain E3 ligase AIP4 to trigger the degradation of MAVS (not shown) along with TRAF-3 and TRAF-6. While ORF6 is reported to antagonize the STAT-1 function by sequestering its nuclear import factors. SARS-ORF-3b, ORF-6, and nucleocapsid protein function to antagonize interferon production. Besides this, the host mRNA destabilizing functions of NSP-1 are also reported. However, Nsp1 protein suppresses IFN-β mRNA accumulation without inhibiting IRF3 dimerization. Similarly, SARS-CoV NSP-15 inhibits MAVS-induced apoptosis sustaining the intracellular viral presence. SARS-CoV N protein can activate AP-1 but not the NF-κB signaling pathway. SARS-CoV proteins have been shown to inhibit the JAK-STAT pathway in the infected cell that responds to the Type-I IFNs secreted from bystander/neighboring cells. STAT-1-STAT-2-heterodimers combines with the IRF-9 to form the ISGF3 complex. This complex is crucial for the activation of genes harboring ISRE in their promoter regions. Viral protein ORF-6 blocks the nuclear import of ISGF3 by reducing the available import factor KPNB1 (Kβ1). Accordingly, various types of the IFNs are secreted from viral-infected cells that may induce various anti-viral restriction factors (such as OAS, PKR, viperin tetherin, IFITM, RNase L, GTPase, TRIM, ADAR1, APOBEC, and others) following binding to their receptors. Coronavirus-derived nonstructural protein also contributes to abrogate IFN expression or IFN-related signaling pathways. SARS-CoV-derived N protein can inactivate anti-virus restriction factor TRIM25 (RING-finger E3 ubiquitin ligase that controls RIG-I ubiquitination and IFN-β production). MAVS/ISP-1-related pathways may cause apoptosis through the induction of the caspasesmitochondria-mediated pathway
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Should we stimulate or suppress immune responses in COVID-19? Cytokine and anticytokine interventions
Imbalanced Host Response to SARS-CoV-2 Drives Development of COVID-19
SARS-CoV-2 ORF3b is a potent interferon antagonist whose activity is further increased by a naturally occurring elongation variant
Type I IFN immunoprofiling in COVID-19 patients
Therapeutic potentials of ginger for treatment of Multiple sclerosis: A review with emphasis on its immunomodulatory, anti-inflammatory and antioxidative properties
Humoral and T cellmediated immune response against trichomoniasis
M1 and M2 macrophage polarization and potentially therapeutic naturally occurring compounds
Macrophage Polarization in Virus-Host Interactions
CD209L (L-SIGN) is a receptor for severe acute respiratory syndrome coronavirus
pH-dependent entry of severe acute respiratory syndrome coronavirus is mediated by the spike glycoprotein and enhanced by dendritic cell transfer through DC-SIGN
A human coronavirus responsible for the common cold massively kills dendritic cells but not monocytes
Delayed induction of proinflammatory cytokines and suppression of innate antiviral response by the novel Middle East respiratory syndrome coronavirus: implications for pathogenesis and treatment
Middle East respiratory syndrome coronavirus shows poor replication but significant induction of antiviral responses in human monocyte-derived macrophages and dendritic cells
Active replication of Middle East respiratory syndrome coronavirus and aberrant induction of inflammatory cytokines and chemokines in human macrophages: implications for pathogenesis
COVID-19 pathophysiology: A review
SARS-CoV-2 invades host cells via a novel route: CD147-spike protein
COVID-19: consider cytokine storm syndromes and immunosuppression
Leukocyte Antigens Influence the Antibody Response to Hepatitis B Vaccine
COVID-19: an Immunopathological View
Antibody-mediated enhancement of disease in feline infectious peritonitis: comparisons with dengue hemorrhagic fever
Antibodydependent enhancement of feline infectious peritonitis virus infection in feline alveolar macrophages and human monocyte cell line U937 by serum of cats experimentally or naturally infected with feline coronavirus
Anti-severe acute respiratory syndrome coronavirus spike antibodies trigger infection of human immune cells via a pH-and cysteine protease-independent FcgammaR pathway
Antibody-dependent infection of human macrophages by severe acute respiratory syndrome coronavirus
Understanding SARS-CoV-2-Mediated Inflammatory Responses: From Mechanisms to Potential Therapeutic Tools
Anti-spike IgG causes severe acute lung injury by skewing macrophage responses during acute SARS-CoV infection
Immunization with SARS coronavirus vaccines leads to pulmonary immunopathology on challenge with the SARS virus
A double-inactivated severe acute respiratory syndrome coronavirus vaccine provides incomplete protection in mice and induces increased eosinophilic proinflammatory pulmonary response upon challenge
Immunization with inactivated Middle East Respiratory Syndrome coronavirus vaccine leads to lung immunopathology on challenge with live virus
Clinical progression and viral load in a community outbreak of coronavirus-associated SARS pneumonia: a prospective study
Antibody responses against SARS coronavirus are correlated with disease outcome of infected individuals
Severe acute respiratory syndrome coronavirus fails to activate cytokine-mediated innate immune responses in cultured human monocyte-derived dendritic cells
SARS-CoV regulates immune function-related gene expression in human monocytic cells
SARS coronavirus spike protein-induced innate immune response occurs via activation of the NF-kappaB pathway in human monocyte macrophages in vitro
Up-regulation of IL-6 and TNF-alpha induced by SARS-coronavirus spike protein in murine macrophages via NF-kappaB pathway
Plasma inflammatory cytokines and chemokines in severe acute respiratory syndrome
Induction of alternatively activated macrophages enhances pathogenesis during severe acute respiratory syndrome coronavirus infection
Comparative analysis of the human macrophage inflammatory protein family of cytokines (chemokines) on proliferation of human myeloid progenitor cells. Interacting effects involving suppression, synergistic suppression, and blocking of suppression
Middle East respiratory syndrome: pathogenesis and therapeutic developments
Productive replication of Middle East respiratory syndrome coronavirus in monocyte-derived dendritic cells modulates innate immune response
Middle East respiratory syndrome coronavirus infection: virus-host cell interactions and implications on pathogenesis
High secretion of interferons by human plasmacytoid dendritic cells upon recognition of Middle East respiratory syndrome coronavirus
Pneumonia from human coronavirus in a macaque model
Clinical features and virological analysis of a case of Middle East respiratory syndrome coronavirus infection
SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor
Immune Responses to SARS-CoV, MERS-CoV and SARS-CoV-2, Advances in experimental medicine and biology
Clinical features of patients infected with 2019 novel coronavirus in
Aberrant pathogenic GM-CSF+ T cells and inflammatory
CD14+CD16+ monocytes in severe pulmonary syndrome patients of a new coronavirus
Pathogenic T cells and inflammatory monocytes incite inflammatory storm in severe COVID-19 patients
The deadly coronaviruses: The 2003 SARS pandemic and the 2020 novel coronavirus epidemic in China
Severe Acute Respiratory Syndrome Coronavirus Viroporin 3a Activates the NLRP3 Inflammasome
The Science Underlying COVID-19: Implications for the Cardiovascular System
Protective role of ACE2 and its downregulation in SARS-CoV-2 infection leading to Macrophage Activation Syndrome: Therapeutic implications
Angiotensin-converting enzyme 2 in severe acute respiratory syndrome coronavirus and SARS-CoV-2: A double-edged sword?
Dynamics of ADAM17-Mediated Shedding of ACE2 Applied to Pancreatic Islets of Male db/db Mice
Tumor necrosis factor-alpha convertase (ADAM17) mediates regulated ectodomain shedding of the severe-acute respiratory syndrome-coronavirus
receptor, angiotensin-converting enzyme-2 (ACE2)
The discovery of angiotensin-converting enzyme 2 and its role in acute lung injury in mice
Pathological inflammation in patients with COVID-19: a key role for monocytes and macrophages
Toll-like receptor 2: An important immunomodulatory molecule during Helicobacter pylori infection
Inflammasome activation and Th17 responses
The important role played by chemokines influence the clinical outcome of Helicobacter pylori infection
Monocytes in rheumatoid arthritis: Circulating precursors of macrophages and osteoclasts and, their heterogeneity and plasticity role in RA pathogenesis
Targeting of tumour-infiltrating macrophages via CCL2/CCR2 signalling as a therapeutic strategy against hepatocellular carcinoma
Targeting Macrophages: Friends or Foes in Disease?
COVID-19 and emerging viral infections: The case for interferon lambda
Drug delivery to macrophages: A review of targeting drugs and drug carriers to macrophages for inflammatory diseases
Manipulating the NF-kappaB pathway in macrophages using mannosylated, siRNA-delivering nanoparticles can induce immunostimulatory and tumor cytotoxic functions
Targeting tumor-associated macrophages with anti-CSF-1R antibody reveals a strategy for cancer therapy
Firstin-Human Study of AMG 820, a Monoclonal Anti-Colony-Stimulating Factor 1 Receptor
Patients with Advanced Solid Tumors
Targeting Macrophages as a Potential Therapeutic Intervention: Impact on Inflammatory Diseases and Cancer
COVID-19: Melatonin as a potential adjuvant treatment
Drug repurposing against COVID-19: focus on anticancer agents
Atovaquone Small Molecule Cytochrome b Antimalarial, Antipneumocystic Repurposing, Clinical Trial (NCT04339426)
Avdoralimab mAb Anti-C5aR Checkpoint-immunotherapies Repurposing
Clinical Trial (NCT04360096)
AVM0703 Small Molecule -Lymphoma, immunostimulation Experimental, Clinical Trial (NCT04366115)
Azithromycin Macrolide antibiotics Bacterial 23S rRNA (50S) SARS-CoV-2 infection Clinical Trials (NCT04338698) / (NCT04324463)
Azoximer bromide Immunomodulator -Damage of the immune system Repurposing
Baricitinib Immunosuppressants JAK-1/2 Rheumatoid arthritis Repurposing, Clinical Trial (NCT04358614)
Bicalutamide Anti-androgens Androgen receptor Prostate Cancer Repurposing, Clinical Trial (NCT04374279)
Chloroquine Small Molecule ACE2, TLR9, GST-1 SARS-CoV-2 Infection Repurposing / Experimental, Numerous CTs Clinical Trial (NCT04333628) / (NCT04349371)
Chlorpromazine Phenothiazine antipsychotics Dopamine receptors Antipsychotic agent, anti-emetic Repurposing
Ciclesonide Corticosteroids Glucocorticoid receptor Perennial allergic rhinitis Repurposing
Cinanserin 5-HT2CR-Antagonist 3C-like Proteinase SARS-CoV/HCoV-229E Experimental in vivo evidence. 39. Clazakizumab mAb Anti-IL-6 Psoriatic arthritis Repurposing
Clevudine Small Molecule HBV polymerase Hepatitis B Repurposing, Clinical Trial (NCT04347915)
Cobicistat CYP3A Inhibitors CYP3A HIV-1 infection Combinatorial Darunavir + Cobicistat
Colchicine Anti-gout agents Microtubule inhibitor Gout Management Repurposing
Danoprevir NS3/4A protease inhibitor Genome polyprotein HCV infection Combinatorial Danoprevir + Ritonavir
Dapagliflozin SGLT2 inhibitors Na/glucose cotransporter 2 Type 2 diabetes mellitus Repurposing
Darunavir Protease inhibitor Gag-Pol proteins HIV-1 infection Clinical Trial (NCT04252274)/(NCT04304053)
DAS-181 Recombinant Proteins Sialic acid Influenza Virus Repurposing
Deferoxamine Chelating agents Fe 2+ Chelating agent Iron or aluminum toxicity Repurposing
Defibrotide ss-Oligos Adenosine receptor A1 Sinusoidal obstruction syndrome Repurposing
Dexamethasone Immunosuppressant Glucocorticoid receptor Bacterial infections Repurposing
Dexmedetomidine Small Molecule α2-adrenergic agonist For sedation of ICU patients Repurposing
54. DFV890 Small Molecule -Multiple indications Repurposing
Disulfiram Small Molecule ADH/ MERS-CoV PL pr Chronic alcoholism Experimental inhibition of SARS-CoV
Dornase alfa R-deoxyribonuclease I DNA Cystic fibrosis Repurposing, Clinical Trial (NCT04359654)
Doxycycline Tetracycline antibiotics 16S ribosomal RNA Bacterial infections Repurposing
Kinase inhibitor PI-3-K γ/δ Chronic lymphocytic leukemia Repurposing
Ebselen Organoselenium drug EPHX2/ COVID-19 M pro --Computer-aided drug design. 60. Eculizumab mAb Complement C5 Paroxysmal nocturnal hemoglobinuria (PNH)
Eicosapentaenoic acid (EPA-FFA)
PUFA Prostaglandin G/H synthase 2 Hyperglyceridemic subjects Repurposing, Clinical Trial (NCT04335032)
EIDD-2801 Isopropylester prodrug Viral error catastrophe SARS-CoV-2
HIV-1 Infection Combinatorial Emtricitabine/tenofovir disoproxil Clinical Trial (NCT04334928)
Escin Saponins (triterpenoid) -Experimental anti-cancer Repurposing
Etoposide Plant alkaloids DNA topoisomerase 2-α Testicular-tumor, SCLC Repurposing
Famotidine H2 blockers Histamine H2 receptor Active gastric ulcer Combinatorial HCQ + Famotidine, CT (NCT04370262)
Fingolimod S1PR modulators S1PR SARS-CoV-2 virus, Multiple SARS-CoV-2 virus infection in MS patients
Fluoxetine SSRIs SLC6A4 Depressive disorder, OCD Repurposing, Clinical Trial (NCT04377308)
Fluvoxamine SSRIs SLC6A4 Obsessive-Compulsive Disorder Repurposing
Fosamprenavir Protease inhibitors HIV-1 protease HIV-1 infection Candidate for 3CL-protease
hnCD16 Fc receptor ADCC induction Cancer Immunotherapy Experimental
Galidesivir Pyrrolopyrimidines RDRP disruption Zaire Ebolavirus Repurposing
Human rsACE2 Recombinant protein Inhibits virus attachment SARS-CoV-2
Hydrocortisone Glucocorticoids Glucocorticoid receptor Reducing inflammation Repurposing
Hydroxychloroquine Small Molecule ACE-2, TLR7, TLR9 Malaria, RA, SLE In vitro SARS-CoV-2 inhibition, effective in COVID-19 patients
Ibrutinib Kinase inhibitors Tyrosine kinase BTK B-cell non-Hodgkin lymphoma Repurposing
Ifenprodil Small Molecule NMDA1; GIRK channels Cerebral vasodilator Repurposing
IFX-1 mAb C5a -Repurposing, Clinical Trial (NCT04333420)
Indomethacin NSAID Prostaglandin G/H synthase 1 RA, ankylosing spondylitis Combinatorial HCQ + Zithromax Oral Product Clinical Trial (NCT04344457)
Isotretinoin Retinoids Retinoic acid receptor γ/α Recalcitrant nodular acne Repurposing
Ivermectin Small Molecule Gly-R-α3, GABA-Rβ3 Intestinal strongyloidiasis Repurposing
Lenalidomide Immunomodulatory drugs Protein cereblon Multiple myeloma Repurposing
Lenzilumab Anti-hu GM-CSF mAb GM-CSF Chronic Myelomonocytic Leukemia Repurposing
Leronlimab mAb CCR5 Anti-HIV
NCT04343651)/(NCT04347239)
Levamisole Antihelmintic nAChRα3 Dukes' stage C colon cancer, melanoma, and head/neck cancer Combinatorial Formoterol + Budesonide
Lidocaine Anesthetics Sodium channels Local Anesthesia Intubation and extubation I patients with COVID-19
Lopinavir Protease inhibitor HIV-1 protease SARS-CoV-2 infection IFN-β1b + lopinavir-ritonavir combination for COVID-19
Interleukin IL-2R Treg induced protection from SARS-CoV2-ARDS Repurposing
LY3127804 mAb Angiopoietin 2 ARDS Repurposing
Antimalarials Fe(II)-protoporphyrin IX Moderate acute malaria Combinatorial Mefloquine + azithromycin +/-tocilizumab Clinical Trial (NCT04347031)
Melatonin Biogenic amine Melatonin receptor type 1A Insomnia Repurposing, Clinical Trial (NCT04353128)
Melphalan Alkylating agent DNA MM, ovarian cancer, melanoma, and amyloidosis Repurposing
Meplazumab Anti-CD147-hu-mAb Interleukin-5 Severe eosinophilic asthma Repurposing
Metenkefalin Opioid growth factor -Experimental anti-tumors Combinatorial metenkefalin + tridecactide
Methylprednisolone Glucocorticoids Glucocorticoid-R COVID-19 Pneumonia Repurposing
Montelukast LTRAs CLR1 Anti-asthma Undetermined
N 4 -Hydroxycytidine Ribonucleoside analogue Viral error catastrophe SARS-CoV-2, MERS-CoV Experimental inhibition
N-803 Small Molecule IL-15 receptor agonist Anti-cancerous Repurposing
Naltrexone Opiate antagonists Delta-type opioid receptor Managing opiate dependence Repurposing, Clinical Trial (NCT04365985)
Naproxen NSAIDs PTGS1 Rheumatoid arthritis Repurposing
Nintedanib Kinase inhibitors Receptor tyrosine kinases Idiopathic pulmonary fibrosis Repurposing, Clinical Trial (NCT04338802)
Nitric Oxide Small Molecule Soluble guanylate cyclase Hypoxic respiratory failure Repurposing, Clinical Trial (NCT04338828)
Nivolumab mAb PD-1 Immune checkpoint therapy Repurposing, Clinical Trial (NCT04343144)
NT-17, IL-7 Interleukin Interleukin-7 receptor
Immunosenescence/stimulation Clinical Trial (NCT04380948)
Olokizumab mAb IL-6 Rheumatoid arthritis Combinatorial with RPH-104, Clinical Trial (NCT04380519)
Oseltamivir Neuraminidase inhibitors Neuraminidase Influenza A and B Combinatorial, Clinical Trial (NCT04338698)
Otilimab mAb -Rheumatoid arthritis Repurposing, Clinical Trial (NCT04376684)
Oxytocin Hormone Oxytocin receptor Labor induction Repurposing
Pegylated IFN-λ IFNs IFN-λR Viral infections/Anti-cancerous Repurposing
Poractant alfa Surfactant -Respiratory Distress Syndrome Repurposing, Clinical Trial (NCT04384731)
Povidone Synthetic polymer -Antiseptic Repurposing
Authors declare that they do not have any conflicts of interest.
The mild and moderate COVID-19 were associated with the effective expression of type I IFNs and ISGs in the lungs. Thus, an appropriate local IFN response in the respiratory system can control SARS-CoV-2 infection accompanied by mild and moderate forms of the disease. However, a lower proportion of the SARS-CoV-2-infected patients exhibit severe symptoms. It was proposed, when the viral load is high and the primary local IFN response is failed, the SARS-CoV-2 enters the blood from the lungs and attacks organs expressing high levels of ACE2. The SARS-CoV-2-infected monocytes and macrophages can produce large amounts of numerous types of pro-inflammatory cytokines and chemokines which contribute to the local tissue inflammation and cytokine storm. Both local tissue inflammation and cytokine storm play a key role in the development of COVID-19-related multi-organ failure which causes death in some COVID-19 patients.Jafarzadeh A. et al.