High Blood Levels of Cyclophilin A Increased Susceptibility to Ulcerative Colitis in a Transgenic Mouse Model.

Mouse models of human autoimmune diseases and inflammation are a challenging field because of the relatively low homology between the human and mouse immune systems. At the same time, inflammation plays a significant role in the pathogenesis of many diseases, strongly impacting quality of life and mortality. Cyclophilin A (CypA) is a pro-inflammatory factor, the ligand of immunosuppressive cyclosporin A, which mediates inflammation through multiple signaling pathways. Here, we describe a novel transgenic mouse model with Cre-dependent expression of the hPPIA gene in vascular endothelium and secretion of CypA into the bloodstream, which shows elevated blood levels of CypA upon activation. Being mostly asymptomatic under standard conditions, these mice exhibited more severe inflammation when provided with 3% dextran sulfate sodium solution instead of drinking water for 7 days. Inflammation symptoms precisely resembled those of ulcerative colitis and included deterioration of the colon crypts alongside the relatively normal duodenum. These results show that the elevated blood level of CypA enhances induced inflammation but does not cause inflammation by itself, suggesting its role in pro-inflammatory positive feedback loops and making CypA a suitable anti-inflammatory target. Moreover, our mouse strain is an applicable colitis model and can be used further in emerging inflammation research and testing anti-CypA targeted therapy.