Targeting PAI-1 signaling results in the enhancement of iTreg and reduction of mortality in a mouse model of septic shock
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1
University of Utah School of Medicine, Department of Internal Medicine, United States
Mycoplasma arthritidis causes arthritis and septic shock 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), is markedly increased in septic shock-susceptible mouse strains injected with live M. arthritidis. We also show that M. arthritidis-infected mice exhibit severe septic shock with elevated levels of inflammatory cytokines TNFa, IL-1b but lower level of TGFb production. Repeated injections of animals with anti-PAI-1 blocking antibody effectively prevent mice from lethal toxicity and suppress production of inflammatory cytokines. Importantly, anti-PAI-1 treatment results in increased level of TGFb and IL-10 expression in livers as well as in lymphoid organs. Parallel results demonstrate that, the expression of Foxp3, a marker of regulatory CD4+ T cells, is significantly increased in anti-PAI-1-injected mice with M. arthritidis infection. Furthermore, the treatment of disease animals with anti-PAI-1 antibody induces tolerogenic DCs that promotes the suppressive function of inducible Treg (iTreg) contributing to the alleviation of mortality and morbidity in septic shock animals. Thus, these results reveal a novel function of PAI-1 in developing septic shock in M. arthritidis-infected mice and suggest a potential therapeutic target for the treatment of inflammatory diseases.
Keywords:
septic shock,
mouse model,
PAI-1,
lethal toxicity,
anti-inflammatory treatment,
tolerogenic DCs,
iTreg,
Therapeutics
Conference:
15th International Congress of Immunology (ICI), Milan, Italy, 22 Aug - 27 Aug, 2013.
Presentation Type:
Abstract
Topic:
Translational immunology and immune intervention
Citation:
Mu
HH,
Nourian
MM and
Huang
Y
(2013). Targeting PAI-1 signaling results in the enhancement of iTreg and reduction of mortality in a mouse model of septic shock.
Front. Immunol.
Conference Abstract:
15th International Congress of Immunology (ICI).
doi: 10.3389/conf.fimmu.2013.02.00044
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Received:
08 Mar 2013;
Published Online:
22 Aug 2013.
*
Correspondence:
Dr. Hong H Mu, University of Utah School of Medicine, Department of Internal Medicine, Salt Lake City, United States, Hong-Hua.Mu@hsc.utah.edu