IL-9 signaling affects central nervous system resident cells during inflammatory stimuli

Abstract

Interleukin (IL) 9, a dominant cytokine in Th9 cells, has been proven to play a pathogenic role in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), by augmenting T cell activation and differentiation; however, whether IL-9 signaling affects central nervous system (CNS)-resident cells during CNS autoimmunity remains unknown. In the present study, we found that the IL-9 receptor (IL-9R) was highly expressed in astrocytes, oligodendrocyte progenitor cells (OPCs), oligodendrocytes and microglia cells, and that its expression was significantly upregulated in brain and spinal cord during EAE. In addition, IL-9 increased chemokine expression, including CXCL9, CCL20 and MMP3, in primary astrocytes. Although IL-9 had no effect on the proliferation of microglia cells, it decreased OPC proliferation and differentiation when in combination with other pro-inflammatory cytokines, but not with IFN-γ. IL-9 plus IFN-γ promoted OPC proliferation and differentiation. These findings indicate that CNS-restricted IL-9 signaling may be involved in the pathogenesis of MS/EAE, thus providing a potential therapeutic target for future MS/EAE treatment through disruption of CNS cell-specific IL-9 signaling.

Neutralization of interleukin‐9 ameliorates experimental stroke by repairing the blood–brain barrierviadown‐regulation of astrocyte‐derived vascular endothelial growth factor‐A

“…Previous studies have shown that in vitro-cultured astrocytes express IL-9R (12). This study verified those results and showed, for the first time to our knowledge, that the astrocyte markers GFAP and IL-9R were colocalized in the brains of rats.…”

“…Our preliminary data demonstrate that IL-9 is highly expressed in peripheral blood mononuclear cells from patients with IS and that IL-9 can aggravate the destruction of the BBB by acting on endothelial cells in the OGD model (11). Additionally, previous studies have suggested that the IL-9 receptor (IL-9R) is highly expressed in astrocytes (12). However, the effect of IL-9 on astrocytes during ischemic brain injury has not been explored.…”

TGF‐β regulation of encephalitogenic and regulatory T cells in multiple sclerosis

“…Another recent study showed that IL‐9 negatively regulates Th17 cells . In addition, IL‐9 levels in the CSF of MS patients were shown to negatively correlate with inflammation, neurodegeneration, and disease progression , supporting a regulatory role for IL‐9 in MS. An in vitro study showed that IL‐9 in the presence of IFN‐γ promotes the proliferation of oligodendrocyte precursor cells, whereas IL‐9 in the presence of IL‐17 inhibits oligodendrocyte precursor cell proliferation, suggesting that Th9 cells may have inverse functions in the presence of Th1 or Th17 cells .…”

Autophagy Modulators Profoundly Alter the Astrocyte Cellular Proteome

“…TNFα, IL2, and IL6 are another set of dysregulated cytokines that play crucial role in synaptic plasticity, homeostatic control, glutamate mediated cytotoxicity, potentiation, sleep, and communication between the immune and endocrine systems [62,64,75]. Further analysis of TNFα is crucial because this cytokine holds a central position in relation to a plethora of CNS conditions, including CNS-TB, autism and multiple sclerosis [64,76,77]. MS patients also demonstrate up-regulation in many of these cytokines in their CSF and serum, all of which are found to be up-regulated upon treatment with BafA1 and some with Rapa (Table 3) [73].…”

“…IL9 receptors are present on astrocytes, oligodendrocytes and microglia, and IL9 dysregulation has been reported in CNS pathologies such as autoimmune encephalitis, oligodendrocyte progenitor cell proliferation and differentiation. Thus, such drug treatment that may mimic these CNS pathologies in patients being administered these drugs, warrants extreme caution and further investigation [77].…”