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-12 and IL-18. IL-12 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-12 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-12/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-12 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- 12/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-12 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-12 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.
This grant will investigate the role of certain inflammatory molecules in the process of diet induced atherosclerosis as well as infection mediated acceleration of atherosclerosis. The overall goal is to design novel therapeutic approaches that will prevent or diminished infection mediated acceleration of vessel inflammation and atherosclerosis.