Background/Purpose: A growing body of evidences indicate that the aberrant activation of innate immune systems, occurring in genetically predisposed patients, drives inflammatory processes in Ankylosing Spondylitis (AS). Aim of this study was to evaluate the activation and the functional relevance of inflammasome pathways in patients with AS.

Methods: Intestinal, synovial and bone marrow expression of inflammasome pathways, pyroptosis and IL-1b and IL-18 was evaluated in AS patients. Analysis of organic acid extraction was performed on ileal samples. The expression of the metabolite-sensing receptors GPR43 and GPR109A involved in the regulation of the intestinal inflammasome was also assessed. The role of intestinal dysbiosis in modulating inflammasome activation was also studied in AS patients and HLA-B27 transgenic rats. Inflammasome activation was evaluated in isolated peripheral AS monocytes. The role of LPS, PGE2 and nicotine in inducing monocyte inflammasome activation and the role of inflammasome in modulating IL-23 production and ILC3 expansion was also evaluated.

Results:

Activation of inflammasomes was observed in the inflamed gut, synovial and bone marrow samples of AS patients and associated with an increased expression of caspase-1, IL-1b and IL-18. In AS, AIM2 expression was observed in the context of tuft cells and of adherent ileal bacteria. Inflammasome activation in AS gut, was associated with the occurrence of dysbiosis and isolated bacteria from the gut of AS patients induced inflammasome activation on isolated PBMC from healthy controls. Increased pyroptosis was also observed in the gut as demonstrated by the membrane localization of Gasdermin D. Isolated intestinal bacteria from AS ileal samples, significantly modulated inflammasome activation in isolated monocytes. Reduced Short-chain fatty acids concentrations and increased expression of GPR43 and GPR109 were demonstrated in the AS ileal samples. Inflammasome activation was also observed in the inflamed gut of HLA-B27 TG rats and suppressed by antibiotics treatment. Increased expression of NLRP3, NLRC4 and AIM2 was confirmed in AS isolated peripheral monocytes, directly correlated with the ASDAS-CRP, and paralleled by increased serum levels of IL-1b. In in vitro studies, LPS and nicotine strongly activated NLRP3, NLRC4 and AIM2 pathways in AS monocytes. The CC genotype of PTGER4 SNP rs6896969 was associated with a significantly increased activation of inflammasome in AS. Inflammasome activation in AS monocytes was required for the induction of IL-23p19 expression in an IL-1b-dependent way. Finally, inflammasome inhibition blocked IL-23-induced ILC3 expansion.

Conclusion:

Inflammasome activation occurs in AS patients and is modulated by a plethora of different tissue-specific and circulating stimuli. Inflammasome drives IL-23p19 production in a IL-1b-dependent mechanism and modulate ILC3 expansion in AS patients possibly representing a future area of therapeutic interventions in AS.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/dysbiosis-dependent-inflammasomes-activation-drives-innate-immune-responses-in-ankylosing-spondylitis-patients/