Trends in Immunology
Feature ReviewSpecial Issue: Microglia and AstrocytesThe Role of Astrocytes in CNS Inflammation
Section snippets
Astrocytes: Once Overlooked, Now Stepping into the Spotlight
Cells in the adult CNS (see Glossary) can be classified in two major groups: neurons and glia. Glial cells (oligodendrocytes, microglia, and astrocytes) share a common feature: they are unable to produce an electrical impulse. Oligodendrocytes are specialized in myelin production, microglia are CNS-resident macrophages, and astrocytes were traditionally viewed as cells involved in supporting neurons. However, it is now clear that astrocytes perform a broad array of functions, including ion and
Astrocyte Heterogeneity
More than 100 years ago, the understanding of the structure and function of the nervous system was revolutionized by the contributions of Camillo Golgi and Santiago Ramon y Cajal (1906 Nobel Prize winners). Golgi developed ‘the black reaction’, a silver staining technique that revealed entire neurons including their processes. Ramon y Cajal would later use this method to provide evidence on the individual nature of nerve cells, a foundational idea of modern neuroscience.
Among many
Reactive Astrocytes
Based on the heterogeneity of astrocytes detected under homeostatic conditions, it is unsurprising that astrocytes mount diverse responses that can contribute to tissue repair and promote CNS pathology in the context of trauma, infection, and neurodegenerative diseases. Thus, astrocyte reactivity is not an all-or-none process; rather, it constitutes a highly heterogeneous process.
One common feature of reactive astrocytes across different species is the upregulation of glial fibrillary acidic
Signaling Pathways Controlling Reactive Astrocytes
Multiple signaling pathways initiate and modulate astrocyte reactivity, including the Janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3) pathway [16,17], the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway [18], the calcineurin (CN) pathway [19], and the mitogen-activated protein kinase (MAPK) pathway [20] (Table 1). Although NF-κB, CN, and MAPK constitute important pathways in the control of reactive astrocytes, they seem to modulate
Astrocytes in the Response against Microbial Infections Targeting the CNS
Many viruses target the human CNS, including the flaviviruses Zika virus (ZIKV), West Nile virus (WNV) and Japanese encephalitis virus (JEV) [31]. Astrocytes in mice and humans express a wide variety of pattern recognition receptors (PRRs) responsive to viral pathogen-associated molecular patterns (PAMPS). In flavivirus-infected cells, double-stranded RNA (dsRNA) – an intermediate product of viral genome replication – is a major PAMP recognized by Toll-like receptor (TLR) 3, retinoic
Astrocytes in MS
MS is an autoimmune disorder targeting the CNS. In most patients, MS initially presents as a relapsing–remitting disease (RRMS) in which episodes of neurological dysfunction (relapses) are followed by a period of partial or full recovery (remission). Adaptive immunity plays a central role in MS pathogenesis, as indicated by the therapeutic success of drugs such as natalizumab, alemtuzumab, rituximab, and ocrelizumab, which target B cells and T cells in RRMS [42]. A significant fraction of RRMS
Control of Astrocyte Responses in MS
From a therapeutic perspective, the identification of these astrocyte activation states and the molecular mechanisms that control them may offer novel targets for the therapeutic control of astrocytes in MS. Below we discuss recent advances on mechanisms associated with the control of astrocytes in MS.
Concluding Remarks
Our understanding of astrocyte heterogeneity remains limited and should be expanded not only to define the breadth of astrocyte activation states but also to identify commonalities among different neurological disorders and processes. In addition, gradients of polarizing factors and cell interactions are likely to be established in different CNS locations to adjust astrocyte activation states to their microenvironments. Hence, it is important to leverage the power of in situ transcriptomics
Acknowledgments
This work was supported by grants NS102807, NS087867, ES02530, AI126880, and AI093903 from the NIH, RSG-14-198-01-LIB from the American Cancer Society, and RG4111A1 and JF2161-A-5 from the National Multiple Sclerosis Society (to F.J.Q.). F.J.Q. received support from the International Progressive MS Alliance (PA-1604-08459). We thank all members of the Quintana laboratory for helpful advice and discussions.
Glossary
- A20
- ubiquitin-editing enzyme encoded by the TNFAIP3 gene, which is a key negative regulator of NF-κB signaling.
- Arborization
- fine, tree-like branching of astrocyte processes.
- Blood–brain barrier (BBB)
- semipermeable barrier in blood vessels vascularizing the CNS; essential for regulation of the exchange of molecules between the CNS and peripheral blood.
- Central nervous system (CNS)
- part of the nervous system comprising the brain and spinal cord.
- Complement
- component of the immune system mediated by
References (133)
The complex STATes of astrocyte reactivity: how are they controlled by the JAK–STAT3 pathway?
Neuroscience
(2016)Involvement of p38 MAPK in reactive astrogliosis induced by ischemic stroke
Brain Res.
(2014)Identification and characterization of MAVS, a mitochondrial antiviral signaling protein that activates NF-κB and IRF 3
Cell
(2005)RNase L activates the NLRP3 inflammasome during viral infections
Cell Host Microbe
(2015)Multiple sclerosis: mechanisms and immunotherapy
Neuron
(2018)- et al.
Induction of classical and nonclassical MHC-I on mouse brain astrocytes by Japanese encephalitis virus
Virus Res.
(2006) Reactive astrocytes in chronic active lesions of multiple sclerosis express co-stimulatory molecules B7-1 and B7-2
J. Neuroimmunol.
(2003)T-cell costimulatory molecules B7-1 (CD80) and B7-2 (CD86) are expressed in human microglia but not in astrocytes in culture
Brain Res.
(1995)Metabolic control of astrocyte pathogenic activity via cPLA2-MAVS
Cell
(2019)- et al.
Environmental control of autoimmune inflammation in the central nervous system
Curr. Opin. Immunol.
(2016)
Astrocyte unfolded protein response induces a specific reactivity state that causes non-cell-autonomous neuronal degeneration
Neuron
Astrocyte glypicans 4 and 6 promote formation of excitatory synapses via GluA1 AMPA receptors
Nature
The Hedgehog pathway promotes blood–brain barrier integrity and CNS immune quiescence
Science
Astrocytes mediate synapse elimination through MEGF10 and MERTK pathways
Nature
Astrocyte-encoded positional cues maintain sensorimotor circuit integrity
Nature
Regional astrocyte allocation regulates CNS synaptogenesis and repair
Science
Identification of diverse astrocyte populations and their malignant analogs
Nat. Neurosci.
Layer-specific morphological and molecular differences in neocortical astrocytes and their dependence on neuronal layers
Nat. Commun.
Brain structure. Cell types in the mouse cortex and hippocampus revealed by single-cell RNA-seq
Science
Astrocyte layers in the mammalian cerebral cortex revealed by a single-cell in situ transcriptomic map
Nat. Neurosci.
Neurons diversify astrocytes in the adult brain through sonic hedgehog signaling
Science
Astrogliosis
Cold Spring Harb. Perspect. Biol.
Neurotoxic reactive astrocytes are induced by activated microglia
Nature
Neuroinflammation and neurodegeneration in human brain at single-cell resolution
Nat. Rev. Immunol.
Effect of DJ-1 on the neuroprotection of astrocytes subjected to cerebral ischemia/reperfusion injury
J. Mol. Med. (Berl.)
STAT3 is a critical regulator of astrogliosis and scar formation after spinal cord injury
J. Neurosci.
Inhibition of astroglial nuclear factor κB reduces inflammation and improves functional recovery after spinal cord injury
J. Exp. Med.
Calcineurin and glial signaling: neuroinflammation and beyond
J. Neuroinflammation
Astroglial inhibition of NF-κB does not ameliorate disease onset and progression in a mouse model for amyotrophic lateral sclerosis (ALS)
PLoS One
Calcineurin triggers reactive/inflammatory processes in astrocytes and is upregulated in aging and Alzheimer’s models
J. Neurosci.
Regulation of the phosphatase calcineurin by insulin-like growth factor I unveils a key role of astrocytes in Alzheimer’s pathology
Mol. Psychiatry
Elusive roles for reactive astrocytes in neurodegenerative diseases
Front. Cell. Neurosci.
The JAK/STAT3 pathway is a common inducer of astrocyte reactivity in Alzheimer’s and Huntington’s diseases
J. Neurosci.
STAT3 labels a subpopulation of reactive astrocytes required for brain metastasis
Nat. Med.
Type I interferons and microbial metabolites of tryptophan modulate astrocyte activity and central nervous system inflammation via the aryl hydrocarbon receptor
Nat. Med.
Tolerogenic nanoparticles inhibit T cell-mediated autoimmunity through SOCS2
Sci. Signal.
Astrocytic A20 ameliorates experimental autoimmune encephalomyelitis by inhibiting NF-κB- and STAT1-dependent chemokine production in astrocytes
Acta Neuropathol.
OTUB1 inhibits CNS autoimmunity by preventing IFN-γ-induced hyperactivation of astrocytes
EMBO J.
Infectious immunity in the central nervous system and brain function
Nat. Immunol.
Cardif is an adaptor protein in the RIG-I antiviral pathway and is targeted by hepatitis C virus
Nature
Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses
Nature
Type I interferons in infectious disease
Nat. Rev. Immunol.
Regional astrocyte IFN signaling restricts pathogenesis during neurotropic viral infection
J. Clin. Invest.
Alpha/beta interferon (IFN-α/β) signaling in astrocytes mediates protection against viral encephalomyelitis and regulates IFN-γ-dependent responses
J. Virol.
Fast type I interferon response protects astrocytes from flavivirus infection and virus-induced cytopathic effects
J. Neuroinflammation
Constitutive aryl hydrocarbon receptor signaling constrains type I interferon-mediated antiviral innate defense
Nat. Immunol.
AHR is a Zika virus host factor and a candidate target for antiviral therapy
Nat. Neurosci.
Regulation of astrocyte functions in multiple sclerosis
Cold Spring Harb. Perspect. Med.
Inhibition of reactive astrocytosis in established experimental autoimmune encephalomyelitis favors infiltration by myeloid cells over T cells and enhances severity of disease
Glia
Reactive astrocytes form scar-like perivascular barriers to leukocytes during adaptive immune inflammation of the CNS
J. Neurosci.
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2024, Seminars in Cell and Developmental BiologyCitation Excerpt :Although studies have shown the interaction of tumor cells with neurons primarily in the gliomas, the biological consequences still need to be elucidated [33]. The astrocytes and microglial cells respond to pathogens or infiltration-induced damage through neuroinflammation [4,34,35]. However, in the case of BrM, the metastatic lesions are also infiltrated by astrocytes and microglial cells, and a cytoprotective interaction between metastasized cancer cells and astrocytes or microglial cells has been confirmed in some studies [36,37].