Innate Immunity and Pathogen mediated Acceleration in Vascular Inflammation

Cedars-Sinai Medical Center, West Hollywood CA

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Abstract

DESCRIPTION (provided by applicant): Chlamydia pneumoniae (CP) is a common respiratory pathogen associated with atypical pneumonia, which has been associated as a trigger or promoter of several chronic inflammatory conditions, such as asthma and atherosclerosis. We have established that CP promotes vascular inflammation and atherosclerosis via a mechanism that depends in part on intact Toll-like receptor (TLR) signaling. Nod (nucleotide oligomerization domain) signaling, via a common kinase called Rip2, acting in synergy with TLRs, can recognize CP as well. We and others have recently established that IL-17A is a proatherogenic cytokine as IL-17A KO mice are protected from diet-and CP induced atherosclerosis. Based upon our preliminary data, Rip2-/- mice have increased atherosclerotic lesion development is due to an increased TH17 response, a novel observation we made in the Rip2-deficient mice. Inflammasomes are cytoplasmic caspase-1 (Casp1)-activating protein complexes that promote maturation and secretion of the proinflammatory cytokines interleukin IL-1ß and IL-18. IL-1ß has long been linked to atherogenesis, but the role of NALP3 inflammasome has only been recently been investigated in high-fat diet induced atherosclerosis in mouse models. Furthermore, IL-1ß is now found to be an important inducer of TH17 responses. The overall goal of the proposed studies is to determine the specific roles of Casp1-dependent- IL-1ß/NALP3 inflammasome pathway as well a NOD/Rip2 signaling pathway (by modulating the IL-17 pathway) in CP-induced acceleration of atherosclerosis and vascular inflammation. Our Central Hypotheses are that pathogens such as CP require the activation of NALP3 inflammasome and Casp1-dependent IL-1ß release to promote infection-mediated acceleration of atherosclerosis; and that the NOD/Rip2 signaling pathway is also involved in CP-induced acceleration of atherosclerosis in an IL-17A dependent mechanism. Specific Aims are: 1- To investigate the role of IL-1ß/inflammasome on CP mediated acceleration of atherosclerosis 2- To investigate the role of Rip2 signaling on the development of atherosclerosis by high fat diet and CP infection-mediated acceleration of atherosclerosis. 3- To determine the role of IL-1ß signaling, Caspase-1, and Rip2 deficiency in hematopoietic versus stromal cells during CP accelerated atherogenesis using Bone Marrow chimeric mice. Significance: At the completion of these studies, we expect to have clarified the relative cellular contributions and the role of NLRP3 inflammasome/ caspase-1-and IL-1ß as well as the role of the NOD/RIP2 signaling pathway intersecting the Th17 axis in pathogen-mediated acceleration of atherosclerosis utilizing the CP infection as a model system. These studies thus may provide potential novel molecular targets to prevent infection-mediated disease progression.