Aryl hydrocarbon receptor (Ahr)-dependent Il-22 expression by type 3 innate lymphoid cells control of acute joint inflammation.

The aryl hydrocarbon receptor (AHR) controls several inflammatory and metabolic pathways involved in various diseases, including the development of arthritis. Here, we investigated the role of AHR activation in IL-22-dependent acute arthritis using the K/BxN serum transfer model. We observed an overall reduction of cytokine expression in Ahr-deficient mice, along with decreased signs of joint inflammation. Conversely, we report worsened arthritis symptoms in Il-22 deficient mice. Pharmacological stimulation of AHR with the agonist VAG539, as well as injection of recombinant IL-22, given prior arthritogenic triggering, attenuated inflammation and reduced joint destruction. The protective effect of VAG539 was abrogated in Il-22 deficient mice. Finally, conditional Ahr depletion of Rorc-expressing cells was sufficient to attenuate arthritis, thereby uncovering a previously unsuspected role of AHR in type 3 innate lymphoid cells during acute arthritis.

NKG2D ligands in inflammatory joint diseases: analysis in human samples and mouse models.

OBJECTIVES: NKG2D ligands (NKG2DLs) are stress-inducible molecules involved in multiple inflammatory settings. In this work, we quantified MICA, an NKG2DL, in the synovial fluid of patients suffering various arthritides and measured Nkg2dLs gene expression in murine models of acute joint inflammation. METHODS: Soluble MICA (sMICA) was quantified by ELISA is synovial fluids harvested from patients suffering osteoarthritis, rheumatoid arthritis, psoriatic arthritis, calcium pyrophosphate crystal arthritis, urate crystal arthritis and reactive arthritis. Transcripts encoding murine NKG2DLs were quantified by RT-qPCR in the joints of mouse models of rheumatoid arthritis, urate crystal arthritis and osteoarthritis. RESULTS: Marked overproduction of sMICA was observed in the synovial fluid of RA patients. Mouse studies highlighted the complex transcriptional regulation of Nkg2d ligands encoding genes depending on the inflammatory setting and microenvironment CONCLUSIONS: sMICA quantification could be an interesting biomarker to identify acute inflammation in RA patients in whom classical markers (i.e. anti-citrullinated protein antibodies, ACPA) are undetectable.

Contrasting role of NLRP12 in autoinflammation: evidence from a case report and mouse models.

OBJECTIVE: To explore at the molecular level the phenotype of a patient suffering an autoinflammatory syndrome which was diagnosed as familial cold autoinflammatory syndrome type 2 (FCAS-2). To explore the functions of Nlrp12 in inflammation using mouse models. METHODS: Whole exome sequencing and Nlrp12 targeted resequencing were performed on DNA isolated from the patient and her family members. In vivo and ex vivo models of inflammation (urate crystals-dependent acute joint inflammation and urate crystals-induced peritonitis) were analysed in Nlrp12-deficient and Nlrp12-competent mice. RESULTS: A rare missense NLRP12 variant (c.857C>T, p.P286L) was identified in the patient and her healthy relatives. Nlrp12-deficient mice exhibit reduced systemic inflammation and neutrophilic infiltration. CONCLUSION: Nlrp12 mediates proinflammatory functions in mice. In humans, the identification of Nlrp12 variants must be cautiously interpreted depending on clinical and paraclinical data to diagnose FCAS-2.