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Balancing the immune response in the brain: IL-10 and its regulation

View Article: PubMed Central - PubMed

ABSTRACT

Background: The inflammatory response is critical to fight insults, such as pathogen invasion or tissue damage, but if not resolved often becomes detrimental to the host. A growing body of evidence places non-resolved inflammation at the core of various pathologies, from cancer to neurodegenerative diseases. It is therefore not surprising that the immune system has evolved several regulatory mechanisms to achieve maximum protection in the absence of pathology.

Main body: The production of the anti-inflammatory cytokine interleukin (IL)-10 is one of the most important mechanisms evolved by many immune cells to counteract damage driven by excessive inflammation. Innate immune cells of the central nervous system, notably microglia, are no exception and produce IL-10 downstream of pattern recognition receptors activation. However, whereas the molecular mechanisms regulating IL-10 expression by innate and acquired immune cells of the periphery have been extensively addressed, our knowledge on the modulation of IL-10 expression by central nervous cells is much scattered. This review addresses the current understanding on the molecular mechanisms regulating IL-10 expression by innate immune cells of the brain and the implications of IL-10 modulation in neurodegenerative disorders.

Conclusion: The regulation of IL-10 production by central nervous cells remains a challenging field. Answering the many remaining outstanding questions will contribute to the design of targeted approaches aiming at controlling deleterious inflammation in the brain.

No MeSH data available.


The role of IL-10 receptor signalling in anti-inflammation. Overview of the IL-10R signalling cascade and the main cellular effects triggered by IL-10
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Fig1: The role of IL-10 receptor signalling in anti-inflammation. Overview of the IL-10R signalling cascade and the main cellular effects triggered by IL-10

Mentions: The manipulation of the balance between protective and degenerative neuroinflammation is gaining importance from a therapeutic point of view. Among the mechanisms in place to avoid exaggerated neuroimmune responses is the production of anti-inflammatory cytokines, such as IL-10. Binding of IL-10 to its receptor triggers a series of signalling cascades mediated by the Janus kinase (JAK) signal transducer and activator of transcription (STAT) pathway, particularly by STAT3 [39]. Signalling through the IL-10 receptor regulates several steps of the immune response, from decreasing cytokine gene expression to down-regulating the expression of major histocompatibility complex class II (MHC-II) and thus antigen presentation to T cells [39, 40]. Furthermore, IL-10 has been shown to prevent apoptosis by activating the phosphatidylinositol-4,5-bisphosphate-3-kinase (PI3K)/Akt cascade and enhancing the expression of anti-apoptotic factors as Bcl-2 and Bcl-xl, whilst attenuating that of caspase-3 [40]. The processes mediated by IL-10 (Fig. 1) have important implications at the CNS level. IL-10 is able to inhibit the production of pro-inflammatory cytokines by microglia, protecting astrocytes from excessive inflammation [41, 42]. IL-10 also acts on astrocytes by potentiating their production of transforming growth factor (TGF)-β [43]. In neurons, IL-10 receptor signalling has been associated with increased cellular survival [44, 45] and the regulation of adult neurogenesis [46, 47]. Thus, IL-10 is an important mediator of the crosstalk between microglia, astrocytes and neurons. Importantly, in addition to the evidence placing IL-10 as a regulator of the immune crosstalk in the CNS, several studies directly implicate defective IL-10 production or signalling in patients and animal models of neurological diseases, ranging from neuropathic pain [48] to multiple sclerosis [49, 50], Alzheimer’s disease [51] or Parkinson’s disease [52].Fig. 1


Balancing the immune response in the brain: IL-10 and its regulation
The role of IL-10 receptor signalling in anti-inflammation. Overview of the IL-10R signalling cascade and the main cellular effects triggered by IL-10
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC5121946&req=5

Fig1: The role of IL-10 receptor signalling in anti-inflammation. Overview of the IL-10R signalling cascade and the main cellular effects triggered by IL-10
Mentions: The manipulation of the balance between protective and degenerative neuroinflammation is gaining importance from a therapeutic point of view. Among the mechanisms in place to avoid exaggerated neuroimmune responses is the production of anti-inflammatory cytokines, such as IL-10. Binding of IL-10 to its receptor triggers a series of signalling cascades mediated by the Janus kinase (JAK) signal transducer and activator of transcription (STAT) pathway, particularly by STAT3 [39]. Signalling through the IL-10 receptor regulates several steps of the immune response, from decreasing cytokine gene expression to down-regulating the expression of major histocompatibility complex class II (MHC-II) and thus antigen presentation to T cells [39, 40]. Furthermore, IL-10 has been shown to prevent apoptosis by activating the phosphatidylinositol-4,5-bisphosphate-3-kinase (PI3K)/Akt cascade and enhancing the expression of anti-apoptotic factors as Bcl-2 and Bcl-xl, whilst attenuating that of caspase-3 [40]. The processes mediated by IL-10 (Fig. 1) have important implications at the CNS level. IL-10 is able to inhibit the production of pro-inflammatory cytokines by microglia, protecting astrocytes from excessive inflammation [41, 42]. IL-10 also acts on astrocytes by potentiating their production of transforming growth factor (TGF)-β [43]. In neurons, IL-10 receptor signalling has been associated with increased cellular survival [44, 45] and the regulation of adult neurogenesis [46, 47]. Thus, IL-10 is an important mediator of the crosstalk between microglia, astrocytes and neurons. Importantly, in addition to the evidence placing IL-10 as a regulator of the immune crosstalk in the CNS, several studies directly implicate defective IL-10 production or signalling in patients and animal models of neurological diseases, ranging from neuropathic pain [48] to multiple sclerosis [49, 50], Alzheimer’s disease [51] or Parkinson’s disease [52].Fig. 1

View Article: PubMed Central - PubMed

ABSTRACT

Background: The inflammatory response is critical to fight insults, such as pathogen invasion or tissue damage, but if not resolved often becomes detrimental to the host. A growing body of evidence places non-resolved inflammation at the core of various pathologies, from cancer to neurodegenerative diseases. It is therefore not surprising that the immune system has evolved several regulatory mechanisms to achieve maximum protection in the absence of pathology.

Main body: The production of the anti-inflammatory cytokine interleukin (IL)-10 is one of the most important mechanisms evolved by many immune cells to counteract damage driven by excessive inflammation. Innate immune cells of the central nervous system, notably microglia, are no exception and produce IL-10 downstream of pattern recognition receptors activation. However, whereas the molecular mechanisms regulating IL-10 expression by innate and acquired immune cells of the periphery have been extensively addressed, our knowledge on the modulation of IL-10 expression by central nervous cells is much scattered. This review addresses the current understanding on the molecular mechanisms regulating IL-10 expression by innate immune cells of the brain and the implications of IL-10 modulation in neurodegenerative disorders.

Conclusion: The regulation of IL-10 production by central nervous cells remains a challenging field. Answering the many remaining outstanding questions will contribute to the design of targeted approaches aiming at controlling deleterious inflammation in the brain.

No MeSH data available.