key: cord-0831943-aimfgxzt
authors: Joshi, Manjunath B.; Kamath, Archana; Nair, Aswathy; YT, Pooja; Sriranjini, Sitaram J.; Gangadharan, G.G.; Satyamoorthy, Kapaettu
title: Modulation of neutrophil (dys)function by Ayurvedic herbs and its potential influence on SARS-CoV-2 infection
date: 2021-03-16
journal: J Ayurveda Integr Med
DOI: 10.1016/j.jaim.2021.03.006
sha: 99516ee14023c68c566d135e52f819243778c60e
doc_id: 831943
cord_uid: aimfgxzt

For centuries, traditional medicines of Ayurveda have been in use to manage infectious and non-infectious diseases. The key embodiment of traditional medicines is the holistic system of approach in the management of human diseases. SARS-CoV-2 (COVID-19) infection is an ongoing pandemic, which has emerged as the major health threat worldwide and is causing significant stress, morbidity and mortality. Studies from the individuals with SARS-CoV-2 infection has shown significant immune dysregulation and cytokine overproduction. Neutrophilia and neutrophil to lymphocyte ratio has been correlated to poor outcome due to the disease. Neutrophils, component of innate immune system, upon stimulation expel DNA along with histones and granular proteins to form extracellular traps (NETs). Although, these DNA lattices possess beneficial activity in trapping and eliminating pathogens, NETs may also cause adverse effects by inducing immunothrombosis and tissue damage in diseases including Type 2 Diabetes and atherosclerosis. Tissues of SARS-CoV-2 infected subjects showed microthrombi with neutrophil-platelet infiltration and serum showed elevated NETs components, suggesting large involvement and uncontrolled activation of neutrophils leading to pathogenesis and associated organ damage. Hence, traditional Ayurvedic herbs exhibiting anti-inflammatory and antioxidant properties may act in a manner that might prove beneficial in targeting over-functioning of neutrophils and there by promoting normal immune homeostasis. In the present manuscript, we have reviewed and discussed pathological importance of NETs formation in SARS-CoV-2 infections and discuss how various Ayurvedic herbs can be explored to modulate neutrophil function and inhibit NETs formation in the context of a) anti-microbial activity to enhance neutrophil function, b) immunomodulatory effects to maintain neutrophil mediated immune homeostasis and c) to inhibit NETs mediated thrombosis.

Coronavirus disease 2019 (COVID-19) by SARS-CoV-2, a plus strand RNA virus, is an ongoing pandemic and is causing respiratory disease associated with pneumonitis. Over the past months, COVID-19 crisis has caused devastating illness globally leading to enormous socio-economic burden. Epidemiological data as on early December , 2020 indicated by world health organization reveals 66,729,375 confirmed cases and 1,535,982 deaths worldwide [1] . Although major sub-group of SARS-CoV-2 infected patients are clinically asymptomatic or minimally symptomatic, approximately 5% patients exhibit significant lung damage and/or multiple organ failure. Critically ill patients infected with SARS-CoV-2 manifest shock, sepsis, localized and systemic coagulopathies and these pathological conditions are significantly associated with acute inflammation [2] . Mechanistically, Angiotensin -Converting Enzyme 2 (ACE2) serves as one of the receptors for SARS-CoV-2 in pulmonary tissues and reduces bioavailability of ACE2 [3] . Decreased ACE2 levels results in the loss of its protective effects by increasing AngII levels, which induces oxidative stress and pro-inflammatory milieu via NADPH oxidase [2] . Increasing evidences suggest that the pandemic causes approximately 10-15% of the patients to progress towards acute respiratory distress syndrome (ARDS) [4] . Characteristically, ARDS shows elevated inflammation in pulmonary tissues, thick mucous secretions in the airways, increased levels of systemic proinflammatory cytokines and extensive lung damage. Taken together, pathogenesis of SARS-CoV-2 comprises bidirectional activation of inflammatory and oxidative stress pathways involving innate immune cells such as neutrophils.

Neutrophils are one of the critical constituents of innate immune system and play a significant role in fighting infections using range of arsenal of antimicrobial functions.

Neutrophils belonging to granulocyte lineage of white blood cells, acts as the first line of defence against pathogens and eliminate them by a) degranulation, b) phagocytosis and c) by producing extracellular traps. Upon stimulation, neutrophils expel their DNA along with histones and granular proteins to form extracellular traps through a process referred as NETosis. Existence of NETs were discovered by Brinkmann et al. (2004) and showed these entities were composed of DNA lattices which trap and eliminate bacteria [5] . NETs are the scaffolds of decondensed chromatin and may contain both nuclear and mitochondrial DNA [6] . Subsequent analysis revealed NETs contained high concentrations of antimicrobial J o u r n a l P r e -p r o o f effectors including variety of proteases, histone variants and anti-bacterial peptides and these may aid in clearing the infection [7] . NETs participate as a defensive action against a broad range of microorganisms including viruses, bacteria, fungi and protozoa [8] .

Variety of viruses have been demonstrated to activate pattern recognition receptors (PPR) in neutrophils to induce NETs formation and more interestingly, signalling effector mediators of virus induced NETs differed from that of bacteria. Upon binding to viral DNA, human immune deficiency virus (HIV-1) induced formation of NETs through endosomal PRR, TLR-7 and TLR-8 [9] . Respiratory syncytial virus fusion protein induced NETs activating TLR-4 [10] . Hantavirus has been demonstrated to form NETs via β2 integrin signalling in human neutrophils [11] . Narayan Moorthy et al. (2013) showed influenza A virus induced NETosis and however these NETs failed to protect against secondary bacterial infection of Pneumococcus [12] . However, virus induced NETs have been shown to act as double edged sword as they possess anti-viral activity and also induce organ damage during viral infections [13] .

Pulmonary inflammation during SARS-CoV-2 infection is characterized by the dysregulated Interestingly, SARS-CoV-2 infected subjects with co-morbid conditions such as diabetes and atherosclerosis are more prone to mortality. Along with pro-inflammatory parameters, abnormal conditions such as disseminated intravascular coagulation [19] , altered conventional coagulation parameters [20] and increase in the thrombus formation under hypoxic conditions [21] are observed in SARS-CoV-2 subjects and these can also be due to the cause or consequences of NETs formation. Neutrophils greatly outnumber other blood mononuclear cells at the site of infection and inflammation can produce reactive oxygen species as well as can release several pro-and anti-inflammatory mediators. Zuo et al. Mounting evidences indicate substantial neutrophil recruitment in infected tissues of COVID-19 subjects (1, 6, 28) . Interestingly, increased components of NETs such as cell free DNA, citrullinated histones and myeloperoxidase-DNA complexes in SARS-CoV-2 infected subjects were observed. Further, authors showed serum from COVID-19 patients induced NETs formation in the neutrophils of healthy subjects [22] .

Several studies have demonstrated that the SARS-CoV-2 infection is associated with Analysis of 150 COVID-19 infected subjects from Wuhan, China, revealed significant elevation of C-reactive protein and IL-6 along with cardiac troponin and myoglobin, indicating a cytokine storm and fulminant myocarditis [35] . Interestingly, IL-6R blocking antibody Tociluzumab was beneficial in reducing immune dysregulation by increasing the lymphocyte count and HLA-DR expression in response to SARS-CoV-2 [36] . Neutrophils are known to shed sIL-6Rα in response to IL-6 [37] and studies have demonstrated the abundance of IL-6 in the SARS-CoV-2-associated cytokine storm [38, 39] . Our earlier studies have shown IL-6 as one of the potential inducer of NETs and during Type 2 Diabetes, glucose modulated IL-6 induced NETs formation [40] . In a model of inflammation, we have also shown that human endothelial cells produce IL-8 during neutrophil-endothelial interactions which is responsible for inducing NETs and these NETs facilitated apoptosis in endothelial cells [41] . Elevated IL-1β in SARS-CoV-2 infected subjects is also known to induce NETs in aortic aneurysms and atherosclerosis [42] [43] [44] [45] . TNF-α has been demonstrated to induce NETs via inducing oxygen free radicals and on the other hand, TNF-α is elevated in serum of SARS-CoV-2 subjects [39, 31] .

NETs formation is a redox sensitive process and requires either oxygen or nitrogen free radicals. Studies have shown involvement of both cytosolic and mitochondrial free radicals in the formation of NETs. Mutation(s) in any gene encoding for subunit of NADPH oxidase manifests in chronic granulomatous disease and infants suffering from this disease do not form intact NETs leading to lung infections [46] . This indicates NADPH derived oxygen free radicals is prerequisite to NETs formation. However, NOX independent NETs have also been demonstrated where mitochondrial ROS was prerequisite to form NETs [47] . Oxidant enzymes such as myeloperoxidase (MPO) is one of the key enzymes in the formation of NETs and MPO knockout mouse models failed to form intact NETs [48] . Reactive nitrogen species has also been shown to induce NETs. Accordingly, in vitro studies have shown antioxidants such as vitamin C, N-acetyl cysteine and enzyme inhibitors significantly abrogate NETs formation [49] .

Over the centuries, Ayurveda the Indian system of medicine, has been in use to treat several infectious and non-infectious diseases. Ayurvedic herbs may significantly contribute towards prophylaxis and clinical management of SARS-CoV-2 infection due to their substantial immunomodulatory properties and re-establishment of immune homeostasis [50] . In the and Alstonia scholaris (Saptaparna) in treating infectious and non-infectious diseases.

Ayurveda recognises communicable disease and epidemics [254] . Table 1 .

Based on Ayurveda scriptures, extensive studies have been carried out to demonstrate antimicrobial properties of Ayurvedic herbs and precisely have shown potential anti-viral effects in in vitro, in vivo and clinical settings [52] [53] [54] [55] [56] . Among them is Terminalia chebula which is widely used for the treatment of upper respiratory infections including cold and cough, and extensive research has shown that the fruit has anti-viral property against influenza A virus [57] . Studies have also demonstrated that treatment with the combination of Acyclovir (ACV) an anti-herpetic agent and T. chebula was effective for treating HSV-1 infection in mouse models [58] . Bioactive molecules such as chebulinic acid and chebulagic acid showed antiviral properties against HSV-2 and HIV [59] .

Aqueous extract of Phyllanthus niruri exhibits strong mitogenic activity against murine lymphocytes and enhances the antigen presentation capability of dendritic cells. 

Over the decades, innumerable studies have reported the anti-oxidant and anti-inflammatory properties of extracts prepared from hundreds of medicinally important plants. In the present manuscript, we have reviewed the Ayurvedic herbs, which significantly modulate neutrophil functions, and also exhibit anti-inflammatory and antioxidant properties. As proinflammatory cytokines induce NETs formation via redox sensitive pathways, we hypothesise that following herbs can be explored to inhibit over-functioning of neutrophils and NETosis, and help in clinical management of SARS-CoV-2 infections. 

Traditional herbal preparations may consist of mixture of macro-and micromolecules which may directly or indirectly activate/inactivate or modify several targets with the fine balance of their PK/PD characteristics. A large array of alkaloids, polyphenols, flavonoids, terpenes, glycosides, saponins and many more may be present depending on the methods of herbal preparation. The constituent bioactive molecules of aforesaid herbs modulating a) neutrophil function, b) immunomodulatory and c) antioxidant properties have been detailed in Table 2 .

These bioactive molecules are subjected to ADME independently or through drug metabolizing enzymes (DMEs). DMEs are broadly categorized into three phases (phase I, II and III) that consists of enzymes and proteins to facilitate mechanisms and functions associated with ADME.

Steroidal alkaloids, sitoindosides VII-X, withaferin A and steroidal lactones extracted from W. somnifera shows significant anti-oxidant and free radical scavenging activities.

Antioxidant enzymes such as catalase, SOD and GP X increased upon the treatment of W. somnifera in rat brain [78] . In inflammatory mouse models induced by monosodium urate, [107] .

The relationship between anti-oxidants and cytokine release is a double edged sword. While oxidants can activate cytokines; under different circumstances, cytokines can also activate oxidants and all of these are driven by several transcriptional and post-transcriptional events.

Both oxidants and cytokines can induce NETosis. Besides, mitochondria also play a central role to maintain the fine balance between reactive oxygen species and cytokine production. It is critical to maintain the neutrophil function such as degranulation, phagocytosis and chemotaxis without excessive NETs formation. In the local microenvironment upon infection and if not adequately oxygenated, infiltration of neutrophils can cause hypoxic conditions due to excess oxygen consumption to release reactive oxygen species [108] .

Hypoxic conditions, such as in ARDS, may inhibit radical formation, extend the life span of neutrophils, yet retain its function to induce degranulation and release pro-inflammatory cytokines [109] . However, these subjects are not within the purview of this review as already a number of articles are published on these topics. Nevertheless, these and more intricate multifactorial imbalances leading to altered phenotypes cannot be restored with a single drug for a normal homeostasis. Therefore, multiple constituents of a single herb or multiple herbs may be required to influence the pathways either sequentially or parallelly to cause induced additive, antagonistic and/or synergistic effects.

Studies suggests potent pro-inflammatory, pro-thrombotic and cytotoxic properties of NETs and their implications in th epathogenesis of thrombosis and associated diseases [110] . On the other hand, recent data indicate COVID-19 pathogenesis is significantly associated with thrombotic microangiopathy via platelet/NETs/thrombin axis [111, 112] . In severe inflammatory conditions of sepsis, activated platelets induced TLR mediated NETs [117] . Examples of representative Ayurvedic herbs containing bioactive molecules might act as a)

anti-viral, b) inhibit formation of NETs by reducing cytokine storm due to the excess release of pro-inflammatory mediators such as IL-6, IL-10, TNF-α, c) reduce NETs formation to decrease platelet aggregation and thrombosis. J o u r n a l P r e -p r o o f Reduces NLRP3 and capase-1 [198] [199]

Berberine Anti-inflammatory Downregulates MCP-1, IL-6, TNF-α Attenuates the inflammation in the air way by inhibiting neutrophil infiltration [200] [201]

Magnoflorine Anti-inflammatory, immuno-modulatory, antioxidant activity [202] J o u r n a l P r e -p r o o f alveolar fluid

Withaferin A Anti-arthritic and anti-inflammatory activities [133] Withanolide E Immunosuppressive effect on human B and T lymphocytes and on mice thymocytes [133] Zingiber officinale

Anti-inflammatory effect without interfering with antigen presenting function of macrophages Suppresses the TNF-α production in TPA-treated female ICR-mice and rats

Inhibits the production of NETs formation and ROS production in response to various lupus stimuli except PMA [208] [89] Emblica officinalis l-ascorbic acid Ascorbic acid infusion abrogates FIP induced NETs production in Vit C deficient Gulo-/-mice [223] J o u r n a l P r e -p r o o f

COVID-19) Dashboard | WHO Coronavirus Disease (COVID-19) Dashboard n

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Grape-seed procyanidins prevent low-grade inflammation by modulating cytokine expression in rats fed a high-fat diet

Anti-inflammatory effect of procyanidins from wild grape (vitis amurensis) seeds in LPS-induced RAW 264.7 cells

Sushruta Samhita of Sushruta, Nidanasthana; Kustha nidana

Charaka Samhita of Agnivesha, Sootrasthana

Linalool Inhibits eosinophil numbers, Th2 cytokines and IgE levels Prevents the influx of inflammatory cells and hyper secretion of mucus

Beta-caryophyllene Inhibits of neutrophil migration in Cg-induced peritonitis mice model Decreases in TNF-α, IFN-γ

+)-alphaphellandrene Prevents induction of Neutrophil accumulation Inhibits TNF-α and IL-6

Reduces total leukocyte and neutrophil count Increases SOD activity Downregulates IL-6, TNF-α and IL-1β

Cinnamaldehyde Reduces neutrophil phagocytosis Increase in IL-8 secretion inhibits PMA induced NETs Hot cinnamon candies blocks NETs progression

Beta-carotene Anti-inflammatory activity by reducing the area of alveolitis and emphysema of lungs Reduces neutrophils and lymphocytes in broncho

Fraxetin Apoptotic inhibition of fraxetin is associated with TNF-α

Scopolamine Inhibits plasma and lung cytokine concentration (IL-10, IL-6 and TNF-α)

Hyoscyamine Penehyclidine hydrochloride a derivative of hyoscyamine attenuated pro-inflammatory cytokines IL-1β, IL-6 and TNF-α

Blocks cytokine release of IL-1, IL-6 and TNF-α Inhibits LPS induced up-regulation of IL-1β, IL-6 and TNF-α with strong down regulation of

Curcumin Regulates both pro and anti-inflammatory factors

Turmerone Reduces IL-1β, TNF-α, IL-6 and MCP-1 in Amyloid β stimulated microglial cells

Piper longum β-caryophyllene Inhibits neutrophil migration in Cg-induced peritonitis mice model Decreases TNF-α, IFN-γ

Guineensine Prevents endotoxemia induced by LPS, reduction in expression of IL-1β

Attenuates inflammatory cell (IL-1β, TNF-α and IL-6) number in BALF, decreases NF-κB protein level in lungs, improves SOD activity, inhibits myeloperoxidase (MPO) activity, inhibits LPSinduced neutrophils

Piperine Reduces expression of IL-6, IL-1β and IgE in ovalbumin induced allergic rhinitis in mice Inhibits LPS-induced IL-1β, TNF-α, IL-6 and PGE2 production in BV2 cells

Hexadecane NETs formation is triggered in neutrophils Induced IL-1β secretion in THP-1 cells. IL-1α was elevated

Piperlongumine Reduces OVA-induced airway inflammatory cell infiltration and Th2 cytokine expression Reduces IgE level and pro-inflammatory cytokine TNF-α, IL-6 and NF-κB activation

Terpinolene Inhibits NO and reduction in O 2 production Inhibits TNF-α and IL-6

Inhibits production of pro-inflammatory cytokines IL-1β, TNF-α and IL-6 in human keratinocyte cell line

Piper nigrum Guineensine Prevents endotoxemia induced by LPS, reduction in expression of IL-1β

Piperine Reduces expression of IL-6, IL-1β and IgE in ovalbumin induced allergic rhinitis in mice Inhibits LPS-induced IL-1β, TNF-α, IL-6 and

Inhibits neutrophil migration in Cg-induced peritonitis mice model Decreases in TNF-α, IFN-γ

28% of α-thujone in Artemisia fukudo inhibits pro-inflammatory cytokines IL-1β, TNF-α and IL-6 in LPS induced macrophages

Allium sativum Diallyl Disulfide Suppresses pro-inflammatory cytokines TNF-α, IL-1β and IL-2, inhibits iNOS

PGE2 by blocking NF-κB Diallyl trisulfide Inhibits LPS-induced iNOS

Allin Inhibits TNF-α and IL-1β in the BALF induced by LPS. Inhibits NF-κB activation

Ajoene Increases levels of INF-γ and IL-12

Allicin Reduces LPS-induced increased pro-inflammatory cytokines TNF-α, IL-1β, IL-6 and NO by HO-1 upregulation Down-regulates TNF-α, IL-1β, IL-6 in dose dependent manner

Adhatoda vasica Vasicine Reduces TNF-α and IL-6

Anthocyanin Inhibits TNF-α, IL-6, IL-8, IL-1β and CCL2

IL-12 (p70), IL-13, Eotaxin and TNF-α secreted by LPS

IL-1β and IL-6 were decreased in LPSstimulates BV2 cells acid Inhibits IL-2, IL-4, IL-6 and IFN-γ

Vitis vinifera Proanthocyanidin Procyanidin Decreases mRNA expressions of IFN-γ, ICAM-1, IL-6, IL-17A, IL1β and TNF-α Decreases pro-inflammatory cytokines TNF-α and IL-6 in mesenteric WAT Inhibits TNF-α and IL-1β expression Suppresses production of NO, PGE 2 and ROS thus suppressing inflammation Suppresses protein expression of iNOS and COX-2

We gratefully acknowledge Centre for Ayurvedic Biology, MAHE, Science and Engineering Board (SERB), Department of Science and Technology (DST), Government of India and MAHE for the support and encouragement.J o u r n a l P r e -p r o o f