Abstract
SKAP1 is an immune cell adaptor that couples the T-cell receptor with the ‘inside-out’ signalling pathway for LFA-1 mediated adhesion in T-cells. A connection of SKAP1 to the regulation of an autoimmune disorder has not previously been reported. In this study, we show that Skap1-deficient (skap1-/-) mice are highly resistant to the induction of collagen-induced arthritis (CIA), both in terms of incidence or severity. Skap1-/- T-cells were characterised by a selective reduction in the presence IL-17+ (Th17) in response to CII peptide and a marked reduction of joint infiltrating T-cells in Skap1-/- mice. SKAP1 therefore represents a novel connection to Th17 producing T-cells and is new potential target in the therapeutic intervention in autoimmune and inflammatory diseases.
Highlights
Rheumatoid arthritis (RA) is a chronic inflammatory disease that affects joints, causing cartilage and bone destruction
LFA-1 on T cells binds ICAM-1/3 on antigen presenting cells [9,10], and its activation involves GTP-binding protein Rac-1 [11,12,13,14,15] and immune cell adaptors in T-cells termed ADAP and SKAP1 (Src-kinase-associated phosphoprotein1 or SKAP-55) [16]
Our finding indicates for the first time a role for SKAP1 in regulating inflammatory arthritis and suggests that the adaptor might serve as a novel therapeutic target
Summary
Rheumatoid arthritis (RA) is a chronic inflammatory disease that affects joints, causing cartilage and bone destruction. The disease can be induced by the immunization of susceptible mice with type II collagen (CII) leading to humoral and cell-mediated responses [1,2]. LFA-1 (lymphocyte function-associated antigen; ␣L2) antagonists reduce inflammation in murine arthritis [8]. LFA-1 on T cells binds ICAM-1/3 on antigen presenting cells [9,10], and its activation involves GTP-binding protein Rac-1 [11,12,13,14,15] and immune cell adaptors in T-cells termed ADAP (adhesion and degranulation-promoting adaptor protein; FYB: Fyn binding protein) and SKAP1 (Src-kinase-associated phosphoprotein or SKAP-55) [16]. Our finding indicates for the first time a role for SKAP1 in regulating inflammatory arthritis and suggests that the adaptor might serve as a novel therapeutic target
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