TRPV4 is a regulator in P. gingivalis lipopolysaccharide-induced exacerbation of macrophage foam cell formation.

Porphyromonas gingivalis (P.g), a major causative agent of periodontitis, has been linked to atherosclerosis, a chronic inflammatory vascular disease. Recent studies have suggested a link between periodontitis and arterial stiffness, a risk factor for atherosclerosis. However, the mechanisms by which P.g infection contributes to atherogenesis remain elusive. The formation of lipid-laden macrophage "foam cells" is critically important to development and progression of atherosclerosis. We have obtained evidence that TRPV4 (transient receptor potential channel of the vanilloid subfamily 4), a mechanosensitive channel, is a regulator of macrophage foam cell formation both in response to P.g-derived lipopolysaccharide (PgLPS) or to an increase in matrix stiffness. Importantly, we found that TRPV4 activity (Ca2+ influx) was increased in response to PgLPS. Genetic deletion or chemical antagonism of TRPV4 channels blocked PgLPS-triggered exacerbation of oxidized LDL (oxLDL)-mediated foam cell formation. Mechanistically, we found that (1) TRPV4 regulated oxLDL uptake but not its cell surface binding in macrophages; (2) reduced foam cell formation in TRPV4 null cells was independent of expression of CD36, a predominant receptor for oxLDL, and (3) co-localization of TRPV4 and CD36 on the macrophage plasma membrane was sensitive to the increased level of matrix stiffness occurring in the presence of PgLPS. Altogether, our results suggest that TRPV4 channels play an essential role in P.g-induced exacerbation of macrophage foam cell generation through a mechanism that modulates uptake of oxLDL.

Association of TNF-alpha (-308 A/G) and IFN-gamma (+874 A/T) gene polymorphisms in response to spontaneous and treatment induced viral clearance in HCV infected multitransfused thalassemic patients.

BACKGROUND: Multitransfused thalassemic individuals are at high risk of developing transfusion transmitted Hepatitis C virus (HCV) infection. The aim of the study was to correlate the effects of host cytokine single nucleotide polymorphisms of TNF-α (-308 A/G) and IFN-γ (+874 A/T) in spontaneous or IFN induced treatment response in the HCV infected thalassemic individuals. METHODS: A total of 427 HCV sero-reactive thalassemic individuals were processed for HCV viral genomic diversity and host gene polymorphisms analysis of TNF-α (-308 A/G) and IFN-γ (+874 A/T). RESULTS: Out of 427 HCV sero-reactive individuals, 69.09% were found to be HCV RNA positive with genotype 3 as the predominant infecting strain (94.29%). Study highlighted that, A allele was significantly associated with (p < .05) spontaneous clearance of HCV infection and G allele was correlated with viral persistence at TNF-α (-308) gene polymorphism. Whereas in case of IFN-γ (+874) SNPs, A allele was significantly responsible (p < .05) for spontaneous clearance than T allele. Our study also indicated that in relapsed cases, IFN-γ (+874) T allele is more responsible than A allele. Though no significant correlation was found at both TNF-α (-308) and IFN-γ (+874) gene polymorphism among SVR and relapsed thalassemic patients. CONCLUSION: A allele at both TNF-α (-308) and IFN-γ (+874) were strongly associated with spontaneous clearance among this population. But in case of SVR and relapsed cases no significant association was found. This cytokine gene polymorphisms pattern will help clinicians to take an informed decision about therapeutic management of HCV infected thalassemic individuals.