TRPV4 is a regulator inP. gingivalislipopolysaccharide‐induced exacerbation of macrophage foam cell formation

Abstract

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 TRPV 4 (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 (Pg LPS ) or to an increase in matrix stiffness. Importantly, we found that TRPV 4 activity (Ca 2+ influx) was increased in response to Pg LPS . Genetic deletion or chemical antagonism of TRPV 4 channels blocked Pg LPS ‐triggered exacerbation of oxidized LDL (ox LDL )‐mediated foam cell formation. Mechanistically, we found that (1) T RPV 4 regulated ox LDL uptake but not its cell surface binding in macrophages; (2) reduced foam cell formation in TRPV 4 null cells was independent of expression of CD 36, a predominant receptor for ox LDL , and (3) co‐localization of TRPV 4 and CD 36 on the macrophage plasma membrane was sensitive to the increased level of matrix stiffness occurring in the presence of Pg LPS . Altogether, our results suggest that TRPV 4 channels play an essential role in P.g‐induced exacerbation of macrophage foam cell generation through a mechanism that modulates uptake of ox LDL .

TRPV4 Plays a Role in Matrix Stiffness-Induced Macrophage Polarization

“…Other reports show that endothelial cells exhibit markedly enhanced proliferation rates when cultured on rigid hydrogels compared to soft hydrogels ( 18 ). Previous reports by our laboratory and others showed that numerous macrophage responses including differentiation, motility, phagocytosis, and proliferation are sensitive to matrix stiffness ( 5 , 6 , 19 – 26 ).…”

“…One focus of this work has been on the role of mechanosensitive ion channels, in particular, the TRP (Transient Receptor Potential) cation channels in many macrophage functions including macrophage polarization spectrum (44)(45)(46)(47). Previous reports by our laboratory and others showed that TRP channel of the vanilloid superfamily 4 (TRPV4) is a ubiquitously expressed, polymodal ion channel that can be activated by a diverse array of biochemical and biophysical stimuli including heat, osmotic stimuli, phorbol derivatives, growth factors, and matrix stiffness (7,9,20,21,25,26,30,(48)(49)(50). TRPV4 is linked to numerous pathophysiological functions including osmolarity sensing, shearstress sensing in arteries, neurological responses, inflammation, tissue fibrosis, and osteogenesis (9,20,21,26,30,(48)(49)(50)(51)(52)(53)(54)(55)(56)(57)(58).…”

“…Previous reports by our laboratory and others showed that TRP channel of the vanilloid superfamily 4 (TRPV4) is a ubiquitously expressed, polymodal ion channel that can be activated by a diverse array of biochemical and biophysical stimuli including heat, osmotic stimuli, phorbol derivatives, growth factors, and matrix stiffness ( 7 , 9 , 20 , 21 , 25 , 26 , 30 , 48 – 50 ). TRPV4 is linked to numerous pathophysiological functions including osmolarity sensing, shear-stress sensing in arteries, neurological responses, inflammation, tissue fibrosis, and osteogenesis ( 9 , 20 , 21 , 26 , 30 , 48 – 58 ). We have recently identified a role of TRPV4 in various macrophage functions such as foam cell formation and foreign body giant cell formation in pathological conditions ( 20 , 21 , 26 , 58 ).…”

“…TRPV4 is linked to numerous pathophysiological functions including osmolarity sensing, shear-stress sensing in arteries, neurological responses, inflammation, tissue fibrosis, and osteogenesis ( 9 , 20 , 21 , 26 , 30 , 48 – 58 ). We have recently identified a role of TRPV4 in various macrophage functions such as foam cell formation and foreign body giant cell formation in pathological conditions ( 20 , 21 , 26 , 58 ). We found that TRPV4-mediated mechanotransduction integrated stiffness and lipopolysaccharide-induced signals to mediate enhanced uptake of oxidized low-density lipoprotein ( 26 ).…”

“…We have recently identified a role of TRPV4 in various macrophage functions such as foam cell formation and foreign body giant cell formation in pathological conditions ( 20 , 21 , 26 , 58 ). We found that TRPV4-mediated mechanotransduction integrated stiffness and lipopolysaccharide-induced signals to mediate enhanced uptake of oxidized low-density lipoprotein ( 26 ). Thus, it seemed possible that TRPV4 played a role in matrix stiffness-induced M1 and M2 polarization spectrum of macrophages.…”