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IL-23 orchestrating immune cell activation in arthritis.

ABSTRACT: IL-23 is a cytokine member of the IL-12 superfamily. These heterodimeric cytokines offer broad immune regulatory activity with potential effector function in inflammatory arthritis. IL-23 is a pro-inflammatory cytokine secreted by dendritic cells and macrophages. It plays a key role in both innate and adaptive immunity. By promoting and maintaining T cell differentiation into Th17 T cells, IL-23 is a key player in the pathogenesis of rheumatic diseases. Data from pre-clinical IL-23 knockout models show the major importance of IL-23 in development of arthritis. The induction and maintenance of type 17 cells, which secrete IL-17A and other pro-inflammatory cytokines, contributes to local synovial inflammation and skin inflammation in PsA, and perhaps in RA. Commensurate with this, therapeutic strategies targeting IL-23 have proven efficient in PsA in several studies, albeit not yet in RA.

SUBMITTER: Najm A

PROVIDER: S-EPMC8527242 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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IL-23 orchestrating immune cell activation in arthritis.

Najm Aurélie A McInnes Iain B IB

Rheumatology (Oxford, England) 20211001 Suppl 4

IL-23 is a cytokine member of the IL-12 superfamily. These heterodimeric cytokines offer broad immune regulatory activity with potential effector function in inflammatory arthritis. IL-23 is a pro-inflammatory cytokine secreted by dendritic cells and macrophages. It plays a key role in both innate and adaptive immunity. By promoting and maintaining T cell differentiation into Th17 T cells, IL-23 is a key player in the pathogenesis of rheumatic diseases. Data from pre-clinical IL-23 knockout mode ...[more]

PMID: 34668017

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Project description:It is very important to understand the communication and interaction mechanisms between the host and its resident microorganisms on host physiology and for precise diagnosis and treatment. Although intestinal fungi and bacteria dysbiosis is increasingly linked to ankylosing spondylitis (AS), their mechanisms of action have been rarely illustrated. In this paper, fecal samples from 10 AS monkeys and 10 healthy controls were collected to systematically characterize the gut mycobiota and microbiota in AS monkeys by 16S rRNA and ITS2 DNA sequencing. Our results showed the gut fungi of Kazachstania pintolopesii, Saccharomycetaceae, Kazachstania, and Saccharomyceteles. Saccharomycetes were specially enriched in AS, and the microbiota of AS monkeys was characterized by an increased abundance of Clostridia, Clostridiales, Ruminococcaceae, and Prevotella 2, using Line Discriminant Analysis Effect Size. Compared to healthy controls, decreased ITS2/16S biodiversity ratios and altered bacterial-fungal interkingdom networks were observed in AS monkeys. Oral administration of K. pintolopesii activates IL-17RA pathway and induce inflammatory reaction in the colonic tissue of C57BL/6 mice, as well as multiple AS phenotypes, including fungal and bacterial dysbiosis, immune responses of NK cells, platelets, T cells, leukocytes, B-cell activation, rheumatoid arthritis, and inflammatory bowel disease. We also found the secreted products of K. pintolopesii could activate the IL-17RA pathway, which induces PANoptosis in macrophage RAW264.7 cells. Much worse, the PANoptosis products could promote the proliferation and morphological changes of K. pintolopesii, which resulted in much more K. pintolopesii and a severe inflammatory reaction. Interestingly, the inflammatory factor TNF-α can promote the morphological transformation of Candida albicans and K. pintolopesii, which is worthy of further study. The characteristic fungi in all these findings implied that fungal and bacterial dysbiosis have a close link to AS and that their communication and interaction indeed play an important role in autoimmune responses, and K. pintolopesii could be a potential marker microorganism in AS, although its specific mechanism is not fully elucidated.

Project description:Reactive arthritis is the development of sterile joint inflammation as a sequel to a remote infection, often in the gut. We have previously shown that a low dose of S. enteritidis inoculated to streptomycin-pretreated mice generates a self-limiting enterocolitis suitable for studying reactive arthritis. Here we show that consumption of Lactobacillus casei prior to infection abolishes intestinal and joint inflammation triggered by Salmonella. BALB/c mice were sacrificed after infection; intestinal and joint samples were analyzed for histological changes and expression of cytokines. TNF-α was measured by ELISA and the expression of IL-1β, IL-6, IL-10, IL-17, IL-23 and TGF-β was assessed by qPCR. L. casei consumption prevented Salmonella-induced synovitis, the increment of TNF-α in knees and the increase of IL-17 expression in popliteal and inguinal lymph nodes. At intestinal level consumption of L. casei drastically diminished S. enteritidis invasiveness and shortened splenic persistence of the pathogen. Bacterial loads recovered at days 2 and 5 from Peyer's patches were 10-fold lower in mice fed with L. casei. In accordance, we found that the augment in gut permeability induced during enterocolitis was decreased in those animals. Consumption of L. casei prior to infection failed to increase anti- inflammatory molecules such as IL-10 and TGF-β in the intestine. On the other hand, consumption of L. casei abrogated the expression of TNF-α, IL-17, IL-23, IL-1β and IL-6 in cecum and mesenteric lymph nodes. These cytokines are needed for differentiation of immune cells involved in the development of reactive arthritis such as Th17 and γδ T cells. Trafficking of these inflammatory cells from the gut to the joints has been proposed as a mechanism of generation of reactive arthritis. Our results suggest that L. casei consumption prevents Salmonella-induced synovitis by altering the intestinal milieu necessary for differentiation of cells involved in the generation of joint inflammation.

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IL-23 orchestrating immune cell activation in arthritis.

Publications

IL-23 orchestrating immune cell activation in arthritis.

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