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IL-11 induces NLRP3 inflammasome activation

ABSTRACT: The objective of this study is to examine IL-11-induced mechanisms of inflammatory cell migration to the CNS. We report that IL-11 is produced at highest frequency by myeloid cells among the PBMC cell subsets. Patients with relapsing-remitting multiple sclerosis (RRMS) have an increased frequency of IL-11+ monocytes, IL-11+ and IL-11R+ CD4+ lymphocytes and IL-11R+ neutrophils in comparison to matched healthy controls (HCs). IL-11+ and GM-CSF+ monocytes, CD4+ lymphocytes, and neutrophils accumulate in the cerebrospinal fluid (CSF). The effect of IL-11 in-vitro stimulation, examined using single cell RNA sequencing (scRNAseq), revealed the highest number of differentially expressed genes (DEGs) in classical monocytes, including upregulated NFKB1, NLRP3 and IL1B. All CD4+ cell subsets had increased expression of S100A8/9 alarmin genes involved in NLRP3 inflammasome activation. In IL-11R+-sorted cells from the CSF, classical and intermediate monocytes significantly upregulated the expression of multiple NLRP3 inflammasome-related genes, including complement, IL18, and migratory genes (VEGFA/B) in comparison to blood-derived cells. Therapeutic targeting of this pathway with aIL-11 mAb in mice with RR experimental autoimmune encephalomyelitis (EAE) decreased clinical scores, CNS inflammatory infiltrates and demyelination. aIL-11 mAb treatment decreased the numbers of NFkBp65+, NLRP3+ and IL-1b+ monocytes in the CNS of mice with EAE. The results suggest that IL-11/IL-11R signaling in monocytes represents a therapeutic target in RRMS.

ORGANISM(S): Homo sapiens

PROVIDER: GSE233917 | GEO | 2023/06/21

REPOSITORIES: GEO

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Project description:Our results introduce interleukin (IL)-11 as a new cytokine that may play a role in the development of the autoimmune response in patients with relapsing remitting multiple sclerosis (RR MS). IL-11 was found to be the highest up-regulated cytokine in the serum and cerebrospinal fluid (CSF) from patients with clinically isolated syndrome (CIS) suggestive of MS. It was also increased in the serum and CSF of patients with clinically definitive RRMS and during the clinical relapses of the disease. CD4+ cells represent a predominant cell source of IL-11 in the peripheral circulation, and the percentage of IL-11+CD4+ cells is significantly increased in CIS patients in comparison to healthy controls (HCs). Furthermore, we have identified IL-11 as a new Th17-promoting cytokine. IL-11 induces a differentiation of naïve CD4+ T cells into Th17 cells, as well as Th17 memory cell expansion, characterized by secretion of IL-17A, IL-17F, IL-21 and IL-22. Since the Th17 cytokines IL-17F, IL-21 and TNF- induced differentiation of naïve cells in the IL-11-secreting CD4+ cells, we propose that cross-talk between IL-11+CD4+ and Th17-cells may play a role in the initiation and propagation of the autoimmune response in RRMS. PBMCs were separated from 15 CIS patients and 7 HCs, and the total RNA was extracted and used for gene array hybridization as described previously. To detect differential gene expression profiles between the CIS patients and HCs, a two class paired test of significance analysis was used. In order to capture complex gene expression changes in the PBMCs derived from 15 CIS patients in comparison to 7 HCs, we performed a comprehensive study using Affymetrix Human Gene array U133 (HG-U133) with 45,000 probe sets representing approximately 33,000 human genes. The arrays were hybridized for 16 h at 45oC in a GeneChip® Hybridization Oven 640 (Affymetrix), washed and stained with R-phycoerythrin streptavidin in a GeneChip® Fluidics Station 400 (Affymetrix). The arrays were scanned with a Hewlett Packard GeneArray Scanner. Affymetrix GeneChip® Microarray Suite 5.0 software was used for washing, scanning, and basic analysis. To detect differential gene expression profiles between the CIS patients and HCs, a two class paired test of significance analysis of microarrays was used. Differentially expressed genes were determined using a Welch two sample t-test. A p<0.05 was considered significant.

Project description:IFNb has been used as a first line therapy for relapsing remitting multiple sclerosis (RRMS). Since only a few studies have addressed the role of endogenous IFNb in the pathogenesis of the disease, our objective was to characterize its role in the transcriptional regulation of pathogenic Th17 cytokines in patients with RRMS. In-vitro studies have demonstrated that IFNb inhibited IL-17A, IL-17F, IL-21, IL-22 and IFN-b secretion in CD4+ lymphocytes through the induction of suppressor of cytokine secretion (SOCS)1 and 3. We found that patients with RRMS have increased serum and cerebrospinal fluid (CSF) Th17 (IL-17A and IL-17F) cytokine levels in comparison to the control subjects, suggesting that deficient endogenous IFNbeta secretion and/or signaling may contribute to the dysregulation of those pathogenic cytokines in CD4+ cells. We identified that the endogenous IFNb from serum of RRMS patients induced a significantly lower IFN-inducible gene expression in comparison to healthy controls (HCs). In addition, in-vitro studies have revealed a deficient endogenous and exogenous IFNb signaling in CD4+ cells derived from MS patients. Interestingly, upon inhibition of the endogenous IFNb signaling by silencing interferon regulatory factor (IRF)7 gene expression, the resting CD4+ T cells secreted significantly higher level of IL-17A, IL-17F, IL-21, IL-22 and IL-9, suggesting that endogenous IFNb suppresses the secretion of these pathogenic cytokines. In-vivo recombinant IFNb-1a treatment induced IFNAR1 and its downstream signaling moleculesM-bM-^@M-^Y gene expression, suggesting that treatment may reconstitute a deficient endogenous IFNbeta regulation of the CD4+ T-cellsM-bM-^@M-^Y pathogenic cytokine production in MS patients. Gene expression changes induced by IFNM-NM-2M-bM-^HM-^R1a were tested using Affymetrix Human Genome U133 (HG-U133) arrays (Affymetrix) that contain 45,000 probe sets representing 39,000 transcripts derived from approximately 33,000 human genes. 107 PBMCs per condition derived from 15 CIS patients were stimulated with plate-immobilized M-NM-1CD3 (1 M-NM-<g/ml) and M-NM-1CD28 (5 M-NM-<g/ml) mAb (BD Biosciences) in the absence or presence of IFNM-NM-2-1a (1000 U/ml) (EMD Serono Inc) for 24 h in serum-free medium (Gibco). Cells were harvested and the total RNA was isolated using a Rneasy kit (Quiagen). Arrays were hybridized for 16 hours at 45oC in the GeneChipM-BM-. Hybridization Oven 640 (Affymetrix). The arrays were washed and stained with R-phycoerythrin streptavidin in the GeneChipM-BM-. Fluidics Station 400 (Affymetrix). The arrays were scanned with a Hewlett Packard GeneArray Scanner. Affymetrix GeneChipM-BM-. Microarray Suite 5.0 software was used for washing, scanning and basic analysis.

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IL-11 induces NLRP3 inflammasome activation

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