key: cord-0027973-8sefzuqj authors: Kim, John; Erice, Clara; Rohlwink, Ursula K.; Tucker, Elizabeth W. title: Infections in the Developing Brain: The Role of the Neuro-Immune Axis date: 2022-02-17 journal: Front Neurol DOI: 10.3389/fneur.2022.805786 sha: 723b22cb2190475de4265134483c67539b76ca94 doc_id: 27973 cord_uid: 8sefzuqj Central nervous system (CNS) infections occur more commonly in young children than in adults and pose unique challenges in the developing brain. This review builds on the distinct vulnerabilities in children's peripheral immune system (outlined in part 1 of this review series) and focuses on how the developing brain responds once a CNS infection occurs. Although the protective blood-brain barrier (BBB) matures early, pathogens enter the CNS and initiate a localized innate immune response with release of cytokines and chemokines to recruit peripheral immune cells that contribute to the inflammatory cascade. This immune response is initiated by the resident brain cells, microglia and astrocytes, which are not only integral to fighting the infection but also have important roles during normal brain development. Additionally, cytokines and other immune mediators such as matrix metalloproteinases from neurons, glia, and endothelial cells not only play a role in BBB permeability and peripheral cell recruitment, but also in brain maturation. Consequently, these immune modulators and the activation of microglia and astrocytes during infection adversely impact normal neurodevelopment. Perturbations to normal brain development manifest as neurodevelopmental and neurocognitive impairments common among children who survive CNS infections and are often permanent. In part 2 of the review series, we broadly summarize the unique challenges CNS infections create in a developing brain and explore the interaction of regulators of neurodevelopment and CNS immune response as part of the neuro-immune axis. The development of the central nervous system (CNS) is a tightly regulated complex and dynamic process. The CNS begins to develop in the third week of gestation and continues to mature postnatally into late adolescence and adulthood (1) . The critical periods of perinatal and early postnatal neurodevelopment, together with adolescent maturation of the brain, are particularly sensitive to environmental influences. Therefore, it is not surprising that CNS infections represent a significant source of mortality and morbidity in children worldwide (2) (3) (4) (5) . In children, these infections lead to devastating neurological sequelae, such as motor deficits or cognitive impairment, that can last a lifetime (6) (7) (8) . Moreover, immunocompromised children are at higher risk of developing more severe CNS infections with poorer outcomes (9) . In this review, we explore the idea that key components of the CNS immune response are also regulators of early neurodevelopment, interacting along the neuro-immune axis. Moreover, we provide an overview of current evidence suggesting that this dual role is a key driver of the unique pediatric (0-18 years) susceptibility to CNS infections and the resultant sequelae. Specifically, we highlight how a dysregulated immune response secondary to two CNS infections cause longterm neurological sequelae. Innate immunity in the CNS begins at the blood-brain barrier (BBB), a semipermeable barrier consisting of brain microvascular endothelial cells (BMECs), stabilized by astrocytic end-feet and pericytes. BMECs line the cerebral vasculature and form a cellular monolayer via tight junctions (TJs) and adherents junctions. The resulting barrier allows for bidirectional regulation of molecular flow and hinders the hematogenous entry of pathogens and toxins (10) . The stage at neurodevelopment where the BBB becomes functional remains unclear. Historically, an immature BBB was considered to contribute to an increased risk of CNS infections in children. This notion can be traced back to early studies of dye-injection experiments and observations of higher cerebrospinal fluid (CSF) protein concentrations in newborn animals (11) . Conclusions on BBB maturity drawn from these experiments, however, have since been challenged, and mounting evidence supports the existence of a functional BBB early in embryonic development (11) . Nevertheless, even a "mature" BBB is not impregnable. The predominant cause of meningitis in older infants and children is Streptococcus pneumoniae, which interacts with the endothelial receptors polymeric immunoglobulin receptor (pIgR) and platelet endothelial cell adhesion molecule-1 (PECAM-1 or CD31) to invade the CNS (12) . The gram-positive bacterium Listeria monocytogenes, a leading cause of meningitis in neonates, enters the CNS by triggering endocytosis in host epithelial cells (13, 14) and hijacking infiltrating monocytes (15) . The protozoan parasite Toxoplasma gondii similarly utilizes this "trojan horse" method of CNS entry via infected dendritic cells and monocytes (16) while also replicating in endothelial cells (17) . Virulence factors which enable host extracellular matrixpathogen interactions and the resulting neuroinflammatory response can also disrupt the BBB at the molecular level. For example, Group B Streptococcus upregulates Snail1 on BMECs which in turn represses the expression of TJ proteins including occludin, zonula occludens, and claudin-5, leading to a leaky BBB (18) . Additionally, the parasite Plasmodium falciparum, the major cause of pediatric cerebral malaria (CM), does not cross the BBB. Rather, P. falciparum binds to endothelial cells, triggering an inflammatory cascade that ultimately leads to BBB damage, vascular leakage, and often lethal cerebral edema (19) . Even peripheral infections such as sepsis can lead to neuroinflammation with similar BBB damage, as demonstrated by the absence of occludin on brain autopsies from septic patients (20) . Once pathogens compromise the BBB or/and enter the CNS, the CNS must mount a sufficient immune response to control the infection. Unfortunately, the host immune response may become dysregulated and initiate various injury cascades that compromise normal neurodevelopment. Recent evidence describing dynamic interactions between the CNS and immune system together with the discovery of the CNS lymphatic system (i.e., glymphatic system and meningeal lymphatics) (21, 22) have rendered it necessary to rethink the long-held notion that the CNS is an immune privileged site (23, 24) . Instead, it is now suggested that the CNS is a site of active, highly regulated immune surveillance (25) . This framework is essential to contextualizing processes whereby microglia, astrocytes, and secreted immune mediators are intimately involved in neurodevelopment (26) (summarized in Figure 1 ). Furthermore, the proliferation and maturation of microglia and astrocytes themselves are shaped by complex local and systemic cues which originate from diverse sources, ranging from the developing CNS itself to the maternal microbiome (27, 28) . In response to key signals including but not limited to transforming growth factor-β (TGF-β) and colony-stimulating factor-1 (CSF-1), microglia undergo distinct, sequential stages of differentiation with morphological, transcriptomic, and functional transformations (29, 30) . Similarly, recent studies have further characterized the temporo-spatial heterogeneity of transcriptomic profiles in astrocytes during perinatal synaptic development (31) , circuitry-specific synaptic association (32), and even throughout normal aging (33, 34) . Amidst the complex milieu that is the developing CNS, further appreciation of the roles of immunologically active glia and signaling molecules in neurodevelopment is quintessential to understanding the susceptibility of the pediatric CNS to infections and devastating sequelae. Microglia are resident immune cells of the CNS and an important defense against invading pathogens and tissue injury. Microglial distribution in the brain is heterogenous, ranging from 0.5 to 16.6% of cells in the parenchyma (35) . The colonization of the developing brain by embryonic microglia precedes neurogenesis, astrogliogenesis, and vasculogenesis, alluding to the crucial role of microglia in mediating early developmental and homeostatic processes of the CNS (36). Microglia are dynamic cells that constantly survey their microenvironment and respond to environmental cues. Under pathological conditions they undergo a phenotypic shift from the ramified (or "quiescent") form to the ameboid (or "activated") form (37) . Their intrinsic role as active surveyors and phagocytes of the brain parenchyma makes microglia key players in synaptic pruning (38) (39) (40) . Synaptic pruning constitutes the elimination of excess connectivity and its functional structures (i.e., synaptic terminals, axonal and dendritic branches), and is a critical process FIGURE 1 | The neuro-immune axis in the developing brain. Astrocytes, microglia, and secreted immune mediators have dual roles during normal brain development and the immune response triggered by CNS infections. During normal brain development, they are integral to synaptic pruning, regulation of dendritic (Continued) Frontiers in Neurology | www.frontiersin.org 3 February 2022 | Volume 13 | Article 805786 FIGURE 1 | growth/morphology, neurogenesis, astrogliogenesis, angiogenesis, myelination, and glial differentiation. However, amid the immune response during infection, brain development becomes dysregulated which can lead to neurological, neurodevelopmental, and psychiatric sequelae. The lower panel summarizes the roles of resident immune cells (microglia and astrocytes) and secreted immune mediators (TNF super family, MMP, IL-6) during normal brain development compared to dysregulated brain development during CNS infection. Abbreviations: BBB, blood-brain barrier; CM, cerebral malaria; CNS, central nervous system; MMP, matrix metalloproteinases; TBM, tuberculous meningitis; TNF, tumor necrosis factor; VEGF, vascular endothelial growth factors. Created with BioRender.com and CorelDRAW Graphics Suite 2021. during the prenatal and postnatal maturation of neural circuitry. Accordingly, depletion of microglia leads to defective pruning in the developing auditory brainstem (41), the visual cortex (42) , and the somatosensory cortex (43) . To date, numerous studies have identified microglia-specific signaling molecules that underpin the normal development of neural circuitry including complement receptor 3-C3 (44), the chemokine CX3CL1-CX3CR1 (45) , and CD47-SIRPα signaling (46) . In order to respond to environmental cues, microglia express extensive molecular tools critical to sampling and interpreting brain milieu. For example, pattern recognition receptors (PRRs) expressed on microglia cell membranes, such as toll-like receptors (TLRs), enable microglia to mount a rapid response to microbial invasion and endogenous cellular damage. These receptors recognize pathogen-associated molecular patterns (PAMPs) and damaged-associated molecular patterns (DAMPs) (47, 48) . Moreover, microglia express a cluster of genes, dubbed the microglial "sensome, " that allow them to sense CNS perturbations and include genes encoding purinergic receptors (e.g., P2RY12, ADORA3, TMEM173), cytokine and chemokine receptors (e.g., CSF1R, TGFBR1, IFNGR1, CX3CR1, CMKLR1), and Fc receptors (e.g., FCGR3, FCER1G) (49, 50) . During CNS infections, microglia clear bacteria via receptormediated phagocytosis (51, 52) , identify and destroy virusinfected neurons (53) , and even pave the way for remyelination post-infection by clearing debris and recruiting oligodendrocytes (54) . In addition, microglia mediate a broader immune response by secreting key signaling molecules including proinflammatory cytokines and chemokines in a pathogen-specific manner. For instance, microglial activation by lipopolysaccharide (LPS) results in significantly different expression of tumor necrosis factor (TNF) and interleukin (IL)-1α/β compared to stimulation by neurotropic Semliki Forest virus (55) . Furthermore, microglia can also cross-present viral antigens from infected neurons to recruit CD8 + T cells (56) and phagocytose infiltrating neutrophils to counteract ischemic injury (57) . Astrocytes comprise up to 30% of the mammalian CNS. Once thought to be mere scaffolds holding neurons together, astrocytes are now recognized for their dynamic roles in BBB maintenance, neuroinflammation, neurotransmission, and other essential CNS processes (58) (59) (60) . Although microglia are important for synaptic pruning, astrocytes are vital to the establishment and fine-tuning of synapses and broader cortical circuitry (61) . Therefore, the role of astrocytes during neurodevelopment has primarily been studied in the context of synaptogenesis and synaptic pruning, leading to the identification of various astrocyte-expressed prosynaptogenic molecules (62) . For example, astrocytic extracellular glycoproteins called thrombospondins (TSPs) have been characterized to promote excitatory synaptogenesis via interaction with the neuronal α2δ-1 receptor (63, 64) . Additionally, the protein SPARCL1 (hevin) is highly expressed by astrocytes during critical periods of early synaptic refinement and is sufficient to selectively induce excitatory synapse formation (65) (66) (67) . Furthermore, astrocytic ephrin-A3 activates EphA4 receptors on neuronal dendritic spines (DS) and regulates DS morphology and lifetime (68, 69) . Notably, many of these molecules are now being examined for their roles during CNS injury and infection. For instance, TSP-1 and TSP-2 are antiangiogenic factors and are upregulated after intracerebral hemorrhage (70) . Astrocytic hevin is also pivotal during synaptic remodeling after ischemic injury in an adult stroke model (71) . This suggests the sustained importance of astrocytes in synapse integrity beyond perinatal and early postnatal neurodevelopment, though the effect of infection warrants further investigation. Astrocytes are also indispensable to CNS innate immunity. They constitute an integral component of the BBB, the first line of defense against pathogen invasion (59) . Ensheathment of cerebral microvasculature by astrocytic terminal processes ("end-feet") is critical to BBB integrity (72) . While neurotropic pathogens can bypass this barrier, its integrity during infection and inflammation remains a crucial bulwark against pathological leukocyte infiltration and hematogenous entry of additional pathogens. During neuroinflammation and ischemia, astrocytes secrete factors such as vascular endothelial growth factors (VEGFs) and matrix metalloproteinases (MMPs), that contribute to BBB disruption (73) (74) (75) (76) . Conversely, astrocyte-derived factors including sonic hedgehog can support BBB recovery (77) . Therefore, astrocytes play a pivotal role in regulating BBB permeability and can help or harm BBB integrity during brain insults. Following infection or injury, astrocytes undergo a morphological, transcriptomic, and functional shift through a process referred to as "reactive astrogliosis" (78) (79) (80) . Reactive astrogliosis is often categorized by the dichotomous A1/A2 system, which many consider too simplistic (80, 81) . Typically, A1 astrocytes upregulate proinflammatory genes which mediate neurotoxic outcomes in response to neuroinflammation, and A2 astrocytes are induced upon ischemic injury and favor a neuroprotective transcriptomic profile that promotes tissue repair. The cytokines TNF, IL-1α, and the complement component 1 subcomponent q (C1q), secreted by activated microglia, robustly induce an A1 phenotype (81) . Interestingly, the A1 shift is associated with alterations in prosynaptogenic factors (i.e., TSP and hevin) which may prove pathological if it occurs during critical periods of neurodevelopment (81) . Similar to microglia, astrocytes express a variety of PRRs such as TLRs, mannose receptor, and nucleotide-binding and oligomerization domain-like receptors (NLRs) which allow them to respond directly to PAMPs and DAMPs (82) . For instance, Staphylococcus aureus infection augments TLR2 mRNA expression in astrocytes, and TLR2 knock out mice exhibit attenuated release of TNF and IL-1β (83) . Pathogenic activation of astrocytic PRRs and downstream immune signaling pathways may, however, pathologically alter neurodevelopment. Astrocytic TLR4 recognizes LPS, which leads to the expression of TNF, IL-15, and IL-27 through TLR4-MyD88 signaling (84) . Early postnatal activation of astrocytic TLR4-MyD88 promotes hippocampal excitatory synaptogenesis and dendritic branching which may underpin increased seizure susceptibility accompanying many CNS infections (85) . During the CNS immune response to infection, microglia, astrocytes, neurons and BMECs secrete a plethora of cytokines, chemokines and MMPs. The roles of these mediators in innate immunity are well documented, therefore, we will concentrate on their involvement during neurodevelopment. Due to the wide breadth of these secreted factors, we will focus on three classical examples: the TNF superfamily (TNFSF), MMPs, and IL-6. The TNFSF consists of 19 cytokines which interact with the TNF receptor superfamily (TNFRSF) (86) . Today, TNFSF/TNFRSF are known to have variegated roles beyond innate immunity and inflammation. Most members of TNFSF and TNFRSF are constitutively expressed in the mammalian CNS and play non-immunological roles critical to healthy brain development such as neuronal and glial cell population control (87) . In addition, they regulate axonal and dendritic growth both in the CNS (88) and peripheral nervous system (89) . TNF, the best understood member of this family, regulates neurogenesis, astrogliogenesis, and angiogenesis (90) (91) (92) . Indeed, TNF −/− mice display reduced numbers of neurons and microglia, and pharmacological TNF inhibition impairs learning and memory in in vivo models (93) . However, human studies have associated chronic expression of TNF with the development and severity of autism and schizophrenia (94) . MMPs are a family of endopeptidases which mediate broad physiological processes (e.g., bone remodeling, wound healing, embryonic development) via the proteolytic cleavage of extracellular matrix proteins, cytokines, and chemokines. Research into the role of MMPs in the developing brain and spinal cord has revealed their homeostatic and spatiotemporal specific expression, and their roles in neuronal migration, proliferation, and myelination (95) (96) (97) (98) (99) . Increased levels of MMP-9, one of the most widely studied MMPs, has been linked to various neurodevelopmental disorders; from autism spectrum disorder (100), Fragile X syndrome (101) , to schizophrenia (102) . In animal models of meningitis, MMP-9 activity has also been shown to contribute to intracerebral hemorrhage and BBB disruption (103, 104) . Similarly, elevated MMP-9 and the ratio of MMP-9 to tissue inhibitor of MMP-1 (TIMP-1) have been observed in the CSF of pediatric patients with bacterial meningitis, including tuberculous meningitis (TBM) (105) (106) (107) . Interestingly, increased MMP-9 during treatment in pediatric TBM patients was associated with improved outcomes, hypothesized to be secondary to MMP's role in neurodevelopment (107) . IL-6 is a cytokine of the interleukin family with both proinflammatory and anti-inflammatory properties that is constitutively expressed at low levels by microglia, neurons, astrocytes, and BMECs (108). In the developing CNS, IL-6 is an essential regulator of neurogenesis (109, 110) and promotor of glial differentiation (111) . Notably, neural stem cells are known to self-regulate progenitor pools via autocrine IL-6 signaling, and transient exposure to increased maternal IL-6 is sufficient to dysregulate neural precursor cell pools in the developing forebrain (112) . Under pathological conditions, IL-6 levels dramatically increase in the CNS and may be neuroprotective. For instance, microglial IL-6 prevents neuronal loss of neural progenitor cells during herpes simplex virus type 1 infection (113) , and endogenous upregulation of IL-6 in response to cerebral ischemia is neuroprotective against excitotoxicity (114) . However, elevated IL-6 levels in the fetal brain after maternal immune activation is a key mediator of transcriptional and behavioral alterations in the adult offspring brain (115, 116) . Both the immune system and neurodevelopment are tightly regulated and versatile processes that must respond to changing microenvironmental cues. Therefore, as outlined above, it is not surprising that they share mechanistic overlap (117) which has left the developing brain vulnerable. It is becoming well accepted that infections during pregnancy and childhood can profoundly affect neurodevelopmental outcome of offspring as well as later in adolescence and adulthood (118) . Below we highlight two CNS infections to exemplify how components of these processes are dysregulated and associated with adverse clinical outcomes. CM is one of the deadliest forms of malaria affecting children under 5 years in low-and middle-income countries (LMICs) disproportionately. Despite aggressive antiparasitic therapy and parasite clearance, over 50% of children surviving CM suffer from neurocognitive deficits, seizures, and neurobehavioral disorders (19, 119, 120) . Both activated microglia and reactive astrocytes have been linked to the pathobiology of CM in both in vivo models and post-mortem human studies (121) . The classical proinflammatory cytokines TNF and IL-6 have also been associated with CM outcomes in human studies (122) . Specifically, higher CSF levels of TNF correlate with coma duration and long-term neurocognitive impairments (123) . Additionally, IL-6 has been linked to severity, where children with CM have increased levels of serum IL-6 compared to those with uncomplicated malaria (124) . TBM is the most aggressive form of extrapulmonary TB. Like CM, children from LMICs are those most at risk. Pediatric survivors of TBM also suffer from neurodevelopmental deficits in locomotor, personal-social, and language function despite intensive antimicrobial treatment (125, 126) . Although numerous factors drive pathogenesis, preclinical and clinical studies suggest the host inflammatory response as a primary contributor to clinical manifestations and sequelae in TBM (127, 128) . A study utilizing a murine model showed uncontrolled tissue pathology without the use of treatment targeting neuroinflammation (129) , and a rabbit model of pediatric TBM has demonstrated elevated levels of activated microglia in the brains of infected rabbits compared to those of healthy rabbits (130) . Furthermore, a study of South African children with TBM performed transcriptomic analysis and found compartmentalized immune response with increased cytokine signaling in lumbar CSF and increased neuronal excitotoxicity associated with glutamate release in ventricular CSF (131) . This glutamate dysregulation within the ventricular milieu may be a manifestation of injury to astrocytes, who are known to be key regulators of glutamate homeostasis (132) . In fact, glial fibrillary acidic protein (GFAP), an astrocyte surface marker, along with neuronal injury biomarkers [e.g., S100B and neuron-specific enolase (NSE)] increased in the CSF of pediatric TBM patients with poor outcomes (133) . While serum S100B levels fail to reflect the progressive injury in TBM (133) , serial measurement of S100B has been proposed to have prognostic value in pediatric patients after traumatic brain injury (134) . Hence, sequential evaluation of plasma/serum S100B may prove more informative in TBM. In both CM and TBM, appropriate antimicrobial therapy does not prevent devastating neurological injury and highlights the need for adjunctive therapy. Currently, there are no approved adjunctive host-directed therapeutics for CM and to date, corticosteroids are the only standard of care host-directed therapy for TBM. Yet, corticosteroids cause side effects and, although they improve TBM mortality, they do not reduce neurological sequelae in survivors and exhibit poor BBB penetration (126, 128, 135, 136) . Modulating chemokine and cytokine responses via monoclonal antibodies is an attractive avenue for treating CNS infections. However, these biologics do not cross the BBB and have not shown conclusive results in clinical trials for sepsis and CM (19) . Understanding the dual role that microglia, astrocytes, and secreted immune mediators play during development and the CNS immune response may additionally aid in identifying novel or repurposed drugs to attenuate neurological sequelae. The window of opportunity may also be greatest in children, as they carry the greatest risk of CNS infection and the greatest need to maintain capacity for proper neurodevelopment. Most importantly, any proposed adjunctive therapeutic should aim to have good BBB penetration, and efforts to overcome this bottleneck via novel drug delivery technologies are ongoing (137) . The developing brain of a child is particularly vulnerable to CNS infections because the cells, molecules and signaling pathways that govern the host response to infection also coordinate key aspects of neurodevelopment. This is evident by the fact that survivors of CNS infections, regardless of etiology, often develop not only neurological disorders but long-term neurological sequelae. Thus, it is imperative to further our understanding of the neuro-immune axis during development to design more effective host-directed adjunctive therapeutics that not only attenuate neuroinflammation but also restore key neurodevelopmental processes. JK, CE, UR, and ET conceptualized the manuscript. JK and CE wrote the initial draft and all coauthors edited the manuscript. ET and UR provided funding. All authors contributed to the article and approved the submitted version. The basics of brain development Bacterial meningitis epidemiology in five countries in the meningitis belt of Sub-Saharan Africa Global, regional, and national burden of meningitis, 1990-2016: a systematic analysis for the Global Burden of Disease Study Epidemiology and etiology of severe childhood encephalitis in the Netherlands Brain abscess in pediatric age: a review. Child's Nervous System Neonatal infection and later neurodevelopmental risk in the very preterm infant The impact of prenatal and neonatal infection on neurodevelopmental outcomes in very preterm infants Perinatal infections and neurodevelopmental outcome in very preterm and very low-birth-weight infants: a meta-analysis Parasitic central nervous system infections in immunocompromised hosts A blood-brain barrier overview on structure, function, impairment, and biomarkers of integrity The rights and wrongs of blood-brain barrier permeability studies: a walk through 100 years of history pIgR and PECAM-1 bind to pneumococcal adhesins RrgA and PspC mediating bacterial brain invasion Mitogen-activated protein kinases are required for effective infection of human choroid plexus epithelial cells by Listeria monocytogenes. Microbes Infect Invasion of the brain by Listeria monocytogenes is mediated by InlF and host cell vimentin The Ly-6Chigh monocyte subpopulation transports Listeria monocytogenes into the brain during systemic infection of mice Use and abuse of dendritic cells by Toxoplasma gondii Endothelial cells are a replicative niche for entry of Toxoplasma gondii to the central nervous system Modeling group B streptococcus and blood-brain barrier interaction by using induced pluripotent stem cell-derived brain endothelial cells. mSphere New insights into microvascular injury to inform enhanced diagnostics and therapeutics for severe malaria Brain tight junction protein expression in sepsis in an autopsy series Structural and functional features of central nervous system lymphatic vessels A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β CNS immune privilege: hiding in plain sight Revisiting the mechanisms of CNS immune privilege Not an immunoprivilaged site anymore but a virtual secondary lymphoid organ Novel roles for immune molecules in neural development: implications for neurodevelopmental disorders Astrocytes and disease: a neurodevelopmental perspective Microbiome influences prenatal and adult microglia in a sex-specific manner Microglia and early brain development: an intimate journey Microglia development and maturation and its implications for induction of microglia-like cells from human iPSCs Activity-dependent modulation of synapse-regulating genes in astrocytes Neural circuit-specialized astrocytes: transcriptomic, proteomic, morphological, and functional evidence Normal aging induces A1-like astrocyte reactivity The aging astrocyte transcriptome from multiple regions of the mouse brain Local distribution of microglia in the normal adult human central nervous system differs by up to one order of magnitude Microglial morphometric parameters correlate with the expression level of IL-1β, and allow identifying different activated morphotypes Microglial interactions with synapses are modulated by visual experience Resting microglia directly monitor the functional state of synapses in vivo and determine the fate of ischemic terminals Microglial P2Y12 is necessary for synaptic plasticity in mouse visual cortex Microglia regulate pruning of specialized synapses in the auditory brainstem Depletion of microglia in developing cortical circuits reveals its critical role in glutamatergic synapse development, functional connectivity, and critical period plasticity GABA-receptive microglia selectively sculpt developing inhibitory circuits Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner Synaptic pruning by microglia is necessary for normal brain development CD47 protects synapses from excess microglia-mediated pruning during development Central role for MyD88 in the responses of microglia to pathogen-associated molecular patterns Microglial diversity by responses and responders The microglial sensome revealed by direct RNA sequencing Analysis of the microglial sensome IgM-dependent phagocytosis in microglia is mediated by complement receptor 3, not Fcα/µ receptor Calreticulin and galectin-3 opsonise bacteria for phagocytosis by microglia Microglia control the spread of neurotropic virus infection via P2Y12 signalling and recruit monocytes through P2Y12-independent mechanisms Microglia depletion exacerbates demyelination and impairs remyelination in a neurotropic coronavirus infection Innate immune response gene expression profiles of N9 microglia are pathogen-type specific T cell engagement of cross-presenting microglia protects the brain from a nasal virus infection Microglia cells protect neurons by direct engulfment of invading neutrophil granulocytes: a new mechanism of CNS immune privilege How do astrocytes shape synaptic transmission? Insights from electrophysiology Astrocytes are necessary for blood-brain barrier maintenance in the adult mouse brain Neuroinflammatory astrocyte subtypes in the mouse brain Astrocytes, neurons, synapses: a tripartite view on cortical circuit development Astrocytes control synapse formation, function, and elimination Thrombospondins are astrocyte-secreted proteins that promote CNS synaptogenesis Gabapentin receptor alpha2delta-1 is a neuronal thrombospondin receptor responsible for excitatory CNS synaptogenesis The role of astrocyte-secreted matricellular proteins in central nervous system development and function Control of excitatory CNS synaptogenesis by astrocyte-secreted proteins Hevin and SPARC SPARCL1 promotes excitatory but not inhibitory synapse formation and function independent of neurexins and neuroligins Control of hippocampal dendritic spine morphology through ephrin-A3/EphA4 signaling Direct astrocytic contacts regulate local maturation of dendritic spines Alteration of thrombospondin-1 and−2 in rat brains following experimental intracerebral hemorrhage: Laboratory investigation Hevin-calcyon interaction promotes synaptic reorganization after brain injury Endothelial Dab1 signaling orchestrates neuro-glia-vessel communication in the central nervous system Astrocyte-derived VEGF-A drives blood-brain barrier disruption in CNS inflammatory disease TLR2-induced astrocyte MMP9 activation compromises the blood brain barrier and exacerbates intracerebral hemorrhage in animal models Matrix metalloproteinase-12 induces blood-brain barrier damage after focal cerebral ischemia Matrix metalloproteinases contribute to the blood-brain barrier disruption during bacterial meningitis Astrocytic sonic hedgehog alleviates intracerebral hemorrhagic brain injury via modulation of blood brain barrier integrity Diverged morphology changes of astrocytic and neuronal primary cilia under reactive insults Genomic analysis of reactive astrogliosis Reactive astrocyte nomenclature, definitions, and future directions Neurotoxic reactive astrocytes are induced by activated microglia Astrocytes are active players in cerebral innate immunity Toll-like receptor 2 (TLR2) mediates astrocyte activation in response to the Grampositive bacterium Staphylococcus aureus Astrocyte TLR4 activation induces a proinflammatory environment through the interplay between MyD88-dependent NFκB signaling, MAPK, and Jak1/Stat1 pathways Postnatal activation of TLR4 in astrocytes promotes excitatory synaptogenesis in hippocampal neurons Beyond cell death: new functions for TNF family cytokines in autoimmunity and tumor immunotherapy The role of tumor necrosis factor receptor superfamily members in mammalian brain development, function and homeostasis How CD40L reverse signaling regulates axon and dendrite growth Regional differences in the contributions of TNF reverse and forward signaling to the establishment of sympathetic innervation Tumor necrosis factor-alpha modulates survival, proliferation, and neuronal differentiation in neonatal subventricular zone cell cultures TNF-α Affects Human Cortical Neural Progenitor Cell Differentiation through the Autocrine Secretion of Leukemia Inhibitory Factor Tumor necrosis factor α primes cerebral endothelial cells for erythropoietin-induced angiogenesis TNF deficiency causes alterations in the spatial organization of neurogenic zones and alters the number of microglia and neurons in the cerebral cortex Cytokines and the neurodevelopmental basis of mental illness MMP-9 (gelatinase B) mRNA is expressed during mouse neurogenesis and may be associated with vascularization Developmental expression of matrix metalloproteinases 2 and 9 and their potential role in the histogenesis of the cerebellar cortex Matrix metalloproteinases and their inhibitors in the developing mouse brain and spinal cord: a reverse transcription quantitative polymerase chain reaction study Myelin formation during development of the CNS is delayed in matrix metalloproteinase-9 and−12 null mice Ontogeny of MMPs and TIMPs in the murine neocortex Amniotic fluid MMP-9 and neurotrophins in autism spectrum disorders: an exploratory study High MMP-9 activity levels in fragile X syndrome are lowered by minocycline MMP9/RAGE pathway overactivation mediates redox dysregulation and neuroinflammation, leading to inhibitory/excitatory imbalance: a reverse translation study in schizophrenia patients Matrix metalloproteinases contribute to brain damage in experimental pneumococcal meningitis Inhibition of matrix metalloproteinases attenuates brain damage in experimental meningococcal meningitis Changes in MMP-9 and TIMP-1 concentrations in cerebrospinal fluid after 1 week of treatment of childhood bacterial meningitis Matrix metalloproteinase (MMP)-8 and MMP-9 in cerebrospinal fluid during bacterial meningitis: association with blood-brain barrier damage and neurological sequelae Elevated matrix metalloproteinase concentrations offer novel insight into their role in pediatric tuberculous meningitis Interleukin-6, a major cytokine in the central nervous system Interleukin-6 and neural stem cells: more than gliogenesis Maternal interleukin-6 hampers hippocampal neurogenesis in adult rat offspring in a sex-dependent manner Microglia-derived interleukin-6 and leukaemia inhibitory factor promote astrocytic differentiation of neural stem/progenitor cells Transient maternal IL-6 mediates long-lasting changes in neural stem cell pools by deregulating an endogenous self-renewal pathway Microglia-induced IL-6 protects against neuronal loss following HSV-1 infection of neural progenitor cells Ischemia-induced interleukin-6 as a potential endogenous neuroprotective cytokine against NMDA receptor-mediated excitoxicity in the brain Maternal immune activation alters fetal brain development through interleukin-6 Maternal immune activation alters behavior in adult offspring, with subtle changes in the cortical transcriptome and epigenome Innate immunity at the crossroads of healthy brain maturation and neurodevelopmental disorders A nationwide study in denmark of the association between treated infections and the subsequent risk of treated mental disorders in children and adolescents Long-term behavioral problems in children with severe malaria Cerebral malaria is associated with long-term mental health disorders: a cross sectional survey of a long-term cohort The potential roles of glial cells in the neuropathogenesis of cerebral malaria Cytokines and chemokines in cerebral malaria pathogenesis. Front Cell Infect Microbiol Elevated cerebrospinal fluid tumour necrosis factor is associated with acute and longterm neurocognitive impairment in cerebral malaria Serum levels of the proinflammatory cytokines interleukin-1 beta (IL-1 beta), IL-6, IL-8, IL-10, tumor necrosis factor alpha, and IL-12(p70) in Malian children with severe Plasmodium falciparum malaria and matched uncomplicated malaria or healthy controls Clinical characteristics and neurodevelopmental outcomes of children with tuberculous meningitis and hydrocephalus Twenty years of pediatric tuberculous meningitis: a retrospective cohort study in the western cape of South Africa Pathogenesis of central nervous system tuberculosis Tuberculous meningitis: a roadmap for advancing basic and translational research Adjunctive role of MMP-9 inhibition along with conventional anti-tubercular drugs against experimental tuberculous meningitis Microglia activation in a pediatric rabbit model of tuberculous meningitis Tuberculous meningitis in children is characterized by compartmentalized immune responses and neural excitotoxicity Astrocytes maintain glutamate homeostasis in the CNS by controlling the balance between glutamate uptake and release Biomarkers of cerebral injury and inflammation in pediatric tuberculous meningitis Prognostic value of serum levels of S100 calciumbinding protein B, neuron-specific enolase, and interleukin-6 in pediatric patients with traumatic brain injury Dexamethasone and long-term outcome of tuberculous meningitis in Vietnamese adults and adolescents Corticosteroids for managing tuberculous meningitis Blood-brain barrier and delivery of protein and gene therapeutics to brain The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.