Suppression of lethal toxicity in Mycoplasma arthritidis-infected mice by blocking PAI-1 is mediated by TLR4-dependent iTreg function (99.28)

Abstract

Abstract Mycoplasma arthritidis causes arthritis and toxic shock syndrome in natural infections of rodents. Here we show that the level of type 1 plasminogen activator inhibitor (PAI-1), the primary inhibitor of tissue-type plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA), are markedly increased in toxic shock-susceptible mouse strains injected with live M. arthritidis. We also showed that M. arthritidis-infected mice exhibited severe toxic shock syndrome with elevated levels of pro-inflammatory cytokines TNFα, IL-1β, but lower levels of TGFβ and IL-10 production. Repeated injections of animals with anti-PAI-1 blocking antibody effectively prevented mice from lethal toxicity and suppressed production of inflammatory cytokines. Importantly, anti-PAI-1 treatment resulted in increased levels of TGFβ and IL-10 expression and production in vivo. Parallel results demonstrated that the expression of Foxp3, GITR and CTLA-4, the signature markers of inducible regulatory T cells (iTreg) in splenic CD4+ cells, were significantly increased in anti-PAI-1-injected mice with M. arthritidis infection. In addition, we also demonstrated that presence of functional TLR4 is indispensable for the induction and function of iTreg in our model system. Thus these results reveal a novel role of PAI-1 and its association with TLR4 in lethal toxicity caused by M. arthritidis, and suggest it could be a potential therapeutic target for the treatment of inflammatory diseases.