Background IL-38 is a newly characterized cytokine that belongs to the IL-1 family. This cytokine is expressed in the rheumatoid arthritis (RA) synovial tissue (1) and IL-38 deficient mice have exacerbated arthritis (2).
Objectives This work aims to analyze the effect of IL-38 overexpression in the joints of arthritic mice, in human macrophages and synovial fibroblasts in vitro.
Methods Articular injections of an adeno-associated virus (AAV2/8) encoding IL-38 were performed in Collagen-Induced Arthritis (CIA), K/BxN Serum Transfer-Induced Arthritis (STIA) and Antigen-Induced Arthritis (AIA) in mice. The effect of IL-38 overexpression was evaluated through clinical scores, immunohistochemistry, microCT, Luminex and RT-qPCR analysis. THP-1 monocytes/macrophages were transduced with a lentiviral vector to overexpress IL-38. Effect of conditioned media from these transduced THP-1 cells was also tested on primary culture: M1 macrophages and fibroblast-like synoviocytes from RA patients (RA-FLS).
Results Clinical inflammatory scores were significantly decreased after AAV IL-38 injection in joints of mice with CIA and STIA, but not AIA. This decrease was accompanied by reduced macrophage infiltration and a decreased expression of Th17 expressed cytokines (IL-17, IL-23, IL-22, TNFα). However, IL-38 overexpression had no effect on cartilage or bone destruction. In vitro, the THP-1 monocytic cell line expressed less IL-6, TNFα and IL-23 after IL-38 overexpression. Conditioned media from these cells, containing released IL-38, was also able to exert an anti-inflammatory effect on human primary M1 macrophages and RA-FLS by reducing their IL-23 (M1) and IL-6 (M1 and RA-FLS) expression.
Conclusions This study shows for the first time that IL-38 overexpression attenuates the severity of experimental arthritis in two mice arthritis models. IL-38 may exert its anti-inflammatory effects by decreasing the production of pro-inflammatory cytokines by macrophages and synovial fibroblasts. This effect can lead to the development of novel treatment strategies in arthritis.
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Disclosure of Interest None declared