IRAK3 is upregulated in Rheumatoid Arthritis synovium and delays the onset of experimental arthritis

Federica Borghese¹Richard O. Williams¹Felix I. L. Clanchy^1,2*

• ¹Kennedy Institute of Rheumatology, University of Oxford, Oxford, England, United Kingdom
• ²Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Medical Sciences Division, University of Oxford, Oxford, England, United Kingdom

TNF is both a potent inducer of endotoxin tolerance-associated molecules, such as IRAK3, and also a therapeutic target in inflammatory auto-immune diseases, as it upregulates the production of inflammatory mediators. The immunomodulatory role of interleukin-1 receptorassociated kinase 3 (IRAK3) was investigated using wild type and IRAK3-deficient mice in collagen induced arthritis (CIA), a murine model of rheumatoid arthritis (RA). As a variant of IRAK3 lacks the death domain required for its canonical role, isoform expression was determined in different inflammatory milieu by immunoblotting; RA synovial explant expression of IRAK3 was measured by qPCR. The role of IRAK3 in experimental arthritis was investigated using WT and IRAK3-deficient mice expressing the A q MHC-II allele. Expression of the larger, "classical" IRAK3 isoform predominated in macrophages treated with various stimuli. Expression of IRAK3 was higher in RA synovium compared to osteoarthritis synovium. Disease progression was significantly accelerated in IRAK3 -/-mice. In addition, circulating levels of IL-1β were greater, and there were fewer Treg both before and after onset of disease. Inflammatory gene expression was higher in the arthritic paws of IRAK3 -/-mice.This study demonstrates IRAK3 deficiency accelerates the progression of arthritis and increases molecular makers of disease severity.