Role of toll like receptor-2 in bacteria andor diet-induced atheroslerosis

Abstract

Accumulating evidence implicates that immune system plays a crucial role in the onset and progression of atherosclerosis. The innate immune system is the first line of defense against invading microorganisms and immune competent cells recognize pathogen-associated molecular patterns on the surface of pathogens through Toll like receptors (TLRs), a family of pattern-recognition receptors. TLRs recruit adaptor molecules to their intracellular signaling domain, leading to the downstream signaling and direct regulation of target immune-responsive genes. Toll like receptor-2 (TLR2) is essential for activation of the innate immune system. Here, we assessed the role of TLR2 as a mediator in high-fat diet and/or pathogen-associated atherosclerosis in an ApoE heterozygous (ApoE[+/-]) murine model. To explore the role of TLR2 in inflammation and infection-associated atherosclerosis, mice genetically deficient in TLR2 were used. The ApoE[+/-]-TLR2[+/+] mice showed a significant increase in atheromatous lesions in the proximal aorta and aortic tree compared to either ApoE [+/-]-TLR2[+/-] or ApoE[+/-]-TLR2[-/-] mice for all conditions (chow diet plus P.gingivalis inoculation, high fat diet plus P. gingivalis inoculation or high fat diet plus vehicle inoculation). In addition, the ApoE[+/-]-TLR2 [+/+] mice displayed profound changes in plaque composition that is characteristic of an unstable plaque phenotype. Increased Serum Amyloid A (SAA) and proinflammatory cytokine levels were also observed in ApoE[+/-]-TLR2[+/+] mice compared to ApoE[+/-]-TLR2[+/-] or ApoE[+/-]-TLR2[-/-] mice irrespective of diet or inoculation which revealed that TLR2 deficiency is accompanied by reduced systemic inflammation. The use of specific TLR2 agonist (FSL-1) in ApoE[+/-] mice led to a significant increase in lesions in the aorta as well as in proximal aorta compared to the TLR2 knock out mice. A profound increase in SAA and other proinflammatory cytokines in the serum were observed in the FSL-1 treated animals when compared to TLR2 deficient mice. Studies involving invasion deficient strain of P. gingivalis (DPG3) or an antibiotic (Metronidazole) to prevent bacterial invasion showed that bacterial invasion plays a crucial role in the initiation and progression of atherosclerosis. Overall, the data from the current study demonstrates that genetic deficiency of TLR2 reduces the progression and extent of atherosclerosis in ApoE[+/-] mice along with change in plaque phenotype.