Role of inter-alpha-trypsin inhibitor heavy chain 4 and its citrullinated form in experimental arthritis murine models

Clin Exp Immunol. 2024 Jan 8:uxae001. doi: 10.1093/cei/uxae001. Online ahead of print.ABSTRACTInter α trypsin inhibitor heavy chain 4 (ITIH4) is a major protein in serum and reported to be up-regulated at the onset of rheumatoid arthritis (RA). Its citrullinated form, cit-ITIH4, is specifically found in serum and synovial fluid of patients with RA. However, the detailed function of ITIH4 in arthritis remains unknown. The aim of this study was to clarify the role of ITIH4 and its citrullinated form using experimental arthritis models. ITIH4 and cit-ITIH4 expression was examined in steady-state mice and two different arthritis models, and their pathological effects were examined in Itih4-deficient mice. In naïve C57BL/6(WT) mice, ITIH4 was expressed as mRNA in the liver and the lung and was expressed as protein in serum and hepatocytes. In K/BxN serum transferred arthritis (K/BxN-STA) and Collagen-induced arthritis (CIA), ITIH4 and its citrullinated form in sera were increased before the onset of arthritis, and cit-ITIH4 was further increased at the peak of arthritis. In Itih4-deficient mice, citrullinated proteins in serum and joints, especially 120kD protein, were clearly diminished; however, there was no significant difference in arthritis severity between WT and itih4-/- mice either in the K/BxN-STA or CIA model. CIA mice also exhibited pulmonary lesions and itih4-/- mice tended to show enhanced inflammatory cell aggregation compared to WT mice. Neutrophils in the lungs o...
Source: Clinical and Developmental Immunology - Category: Allergy & Immunology Authors: Source Type: research