Abstract 16832: A Protective Role for Toll like Receptor 4 in Pathogen-Mediated Atherosclerosis
Endogenous and exogenous ligands of microbial origin stimulate inflammation associated with atherosclerosis progression via the innate immune Toll like receptors (TLRs). The oral pathogen Porphyromonas gingivalis induces inflammatory oral bone destruction manifested as periodontal disease, a common chronic disease. P. gingivalis-mediated periodontal disease is now recognized as a risk factor for systemic inflammatory diseases including, diabetes, stroke, and atherosclerotic and cardiovascular diseases. We have previously demonstrated that TLR2 deficiency diminished P. gingivalis-mediated atherosclerosis in an ApoE-/-mouse model. In the current study we demonstrate that TLR4 plays a protective role in P. gingivalis induced atherosclerosis. ApoE-/- and Apoe-/-TLR4-/- mice on normal chow diet were orally challenged with P. gingivalis or saline 5 times / week for 3 weeks. Thirteen weeks after the last challenge, plaque and inflammatory cell accumulation was analyzed in aortic tissue. Plaque area (%) and accumulation of macrophages, CD8+ T cells, and IL-17+ cells in aortic plaque were significantly greater in P. gingivalis-infected ApoE-/-TLR4 -/- compared to ApoE-/- mice. TLR4 deficiency was associated with a skewing of the adaptive response to P. gingivalis from a Th1 to a Th17 response with a dysregulation in the production of proinflammatory and immunoregulatory cytokines associated with CD8+ T cell responses. MRA imaging revealed greater luminal narrowing in innominate artery of P. gingivalis-infected ApoE-/- TLR4-/- compared to ApoE-/- mice. Our results are in contrast to studies demonstrating decreased atherosclerosis in ApoE-/-TLR4-/- mice fed a high fat diet. These results support the emerging view that oral bacteria contribute to chronic inflammation at sites distant from infection and establish microbial specific TLR4 signaling as a critical determinant of chronic inflammation associated with atherosclerosis progression.
- © 2011 by American Heart Association, Inc.