Astrocyte‐targeted IL‐10 production decreases proliferation and induces a downregulation of activated microglia/macrophages after PPT

Abstract

When central nervous system (CNS) homeostasis is altered, microglial cells become rapidly activated, proliferate and release a broad range of molecules. Among the plethora of molecules involved in the regulation of microglial activation, cytokines are considered crucial. Although production of interleukin‐10 (IL‐10) has been demonstrated after different types of CNS injuries and associated with protective functions, the specific role played by IL‐10 modulating microglial cells remains unclear. Hence, the objective of this study was to evaluate the effects of transgenic astrocyte IL‐10 production on microglial activation associated with axonal anterograde degeneration. To address it, the hippocampal area subjected to perforant pathway transection (PPT) was analyzed by immunohistochemistry (IHC), flow cytometry and protein microarray in transgenic (GFAP‐IL10Tg) mice and their corresponding wild types (WT) littermates. Our results demonstrated increased microglial/macrophages density in nonlesioned and PPT‐lesioned GFAP‐IL10Tg animals when compared with nonlesioned and lesioned WT, respectively. This increase was not due to proliferation, as GFAP‐IL10Tg mice showed a reduced proliferation of microglial cells, but was related to an increased population of CD11b+/CD45high monocyte/macrophages. Despite this higher number, the microglia/macrophage population in transgenic animals displayed a downregulated phenotype characterized by lower MHCII, ICOSL, and CD11c. Moreover, a sustained T‐cell infiltration was found in transgenic animals. We strongly suggest these modifications must be associated with indirect effects derived from the influence of IL‐10 on astrocytes and/or neurons, which express IL‐10R. We finally suggested that TGF‐β produced by astrocytes, along with IL‐2 and CXCL10 might be crucial molecules mediating the effects of transgenic IL‐10.

Aggravated brain injury after neonatal hypoxic ischemia in microglia-depleted mice

“…Previous studies have also indicated that microglia is a major source of locally produced TGF-β after HI insult [63]. However, consistent with our findings, other cells have been reported to be produced after microglia depletion [64]. Taken together, our findings indicate that microglial depletion aggravates neuronal death due to a lack of anti-inflammatory cytokines.…”

Nitric Oxide/Cyclic GMP-Dependent Calcium Signalling Mediates IL-6- and TNF-α-Induced Expression of Glial Fibrillary Acid Protein

“…Indeed, IL-4 and IL-10, a product of macrophages, microglia and lymphocytes, once generated, inhibit the release of pro-inflammatory cytokines from the same cells, resulting in indirect downregulation of astrocyte reactivity (Harry and Kraft 2008). Moreover, alterations in brainderived IL-2 and IL-2 receptors, potentially produced by neurons and astrocytes (Shen et al 2010), have been implicated in the pathogenesis of several major neurological disorders due to their immunoregulatory functions (Wei et al 2014); among these, the ability to drive GFAP+ astrocyte-targeted production of IL-10, which in turn modulates the numbers of microglia/ macrophages, has been postulated (Recasens et al 2019). Therefore, it would be interesting to investigate whether opposite regulation of the identified signalling by functionally different cytokines might be involved in modulating astrocyte reactivity, especially when considering that neuroinflammation associated with neurodegenerative diseases (AD, PD, multiple sclerosis, amyotrophic lateral sclerosis and ischemia) constitutes a superimposed exacerbating factor.…”

Short and long TNF‐alpha exposure recapitulates canonical astrogliosis events in human‐induced pluripotent stem cells‐derived astrocytes

“…IL‐6, IL‐2, and IL‐4 were described in this article as modulatory cytokines because they may induce and terminate inflammatory responses depending on the context of inflammation (Hoyer, Dooms, Barron, & Abbas, ; Luzina et al, ; Rothaug, Becker‐Pauly, & Rose‐John, ). These three cytokines are able to modulate microglial function (Akhmetzyanova, Kletenkov, Mukhamedshina, & Rizvanov, ; Recasens, Shrivastava, Almolda, Gonzalez, & Castellano, ; Rossi et al, ) as well as astrocyte activation (Alves et al, ; Brodie, Goldreich, Haiman, & Kazimirsky, ; Klein et al, ). Diapedesis and activation of other immunocompetent cells like neutrophils and lymphocytes within the brain can also be regulated by these modulatory cytokines (Erta, Quintana, & Hidalgo, ; Gadani, Cronk, Norris, & Kipnis, ; Gao et al, ).…”