Interleukin-22 is increased in multiple sclerosis patients and targets astrocytes

Abstract

BackgroundIncreasing evidences link T helper 17 (Th17) cells with multiple sclerosis (MS). In this context, interleukin-22 (IL-22), a Th17-linked cytokine, has been implicated in blood brain barrier breakdown and lymphocyte infiltration. Furthermore, polymorphism between MS patients and controls has been recently described in the gene coding for IL-22 binding protein (IL-22BP). Here, we aimed to better characterize IL-22 in the context of MS.MethodsIL-22 and IL-22BP expressions were assessed by ELISA and qPCR in the following compartments of MS patients and control subjects: (1) the serum, (2) the cerebrospinal fluid, and (3) immune cells of peripheral blood. Identification of the IL-22 receptor subunit, IL-22R1, was performed by immunohistochemistry and immunofluorescence in human brain tissues and human primary astrocytes. The role of IL-22 on human primary astrocytes was evaluated using 7-AAD and annexin V, markers of cell viability and apoptosis, respectively.ResultsIn a cohort of 141 MS patients and healthy control (HC) subjects, we found that serum levels of IL-22 were significantly higher in relapsing MS patients than in HC but also remitting and progressive MS patients. Monocytes and monocyte-derived dendritic cells contained an enhanced expression of mRNA coding for IL-22BP as compared to HC.Using immunohistochemistry and confocal microscopy, we found that IL-22 and its receptor were detected on astrocytes of brain tissues from both control subjects and MS patients, although in the latter, the expression was higher around blood vessels and in MS plaques.Cytometry-based functional assays revealed that addition of IL-22 improved the survival of human primary astrocytes. Furthermore, tumor necrosis factor α-treated astrocytes had a better long-term survival capacity upon IL-22 co-treatment. This protective effect of IL-22 seemed to be conferred, at least partially, by a decreased apoptosis.ConclusionsWe show that (1) there is a dysregulation in the expression of IL-22 and its antagonist, IL-22BP, in MS patients, (2) IL-22 targets specifically astrocytes in the human brain, and (3) this cytokine confers an increased survival of the latter cells.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-015-0335-3) contains supplementary material, which is available to authorized users.

The Links Between the Gut Microbiome, Aging, Modern Lifestyle and Alzheimer's Disease

“…In a similar study, microbial amyloid was shown to be able to activate T-lymphocytes and induce the production of pro-inflammatory interleukins IL-17A and IL-22 (Nishimori et al, 2012). These cytokines are able to penetrate the blood-brain barrier and cause the production of reactive oxygen species, activation of the TLR2/1 and NFÎB signaling pathways in microglia and astrocytes, which is directly related to neuroinflammation and neurodegeneration (Perriard et al, 2015;Sun et al, 2015;Zhan et al, 2018). Besides Chen et al demonstrated that oral contamination of old rats (previously subjected to antibiotic treatment) with wild E. coli strain, capable of producing the functional curli peptide, led to an increase in brain tissue microgliosis and astrogliosis and increased expression of TLR2, IL6, and TNF (Chen et al, 2016a).…”

IL-22 hinders antiviral T cell responses and exacerbates neurological disorders in ZIKV-infected immunocompetent neonatal mice

“…Whether IL-22 can directly affect glial cells and regulate cell function is not entirely clear. IL-22 receptor was detected in human astrocytes of both healthy controls and multiple sclerosis patients, and IL-22 treatment reduced TNF-α-induced apoptosis of astrocytes [16]. In addition, exogenous IL-22 also promoted the proliferation of human glial cells accompanied by an anti-apoptotic effect [50].…”

“…In a lethal West Nile virus (WNV) encephalitis mouse model, IL-22 de ciency resulted in reduced viral load, decreased in ammatory in ltration and alleviated tissue pathology [15]. In addition, IL-22 was increased in multiple sclerosis patients [16] and could disrupt blood-brain barrier (BBB) tight junctions [17]. These studies suggest that IL-22 may play a detrimental role in the central nervous system (CNS) during viral infection.…”

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“…The serum IL-22 level is increased during relapse in relapsing-remitting MS patients compared to healthy controls, in patients with remission and those with primary progressive MS (ref. 21 ). Similarly, an increase in CD4 + IL-22 + percentage in peripheral blood was observed by N. Muls et al during relapse when compared to remission 22 .…”