title: Reduced endoplasmic reticulum stress-induced apoptosis and impaired unfolded protein response in TRPC3-deficient M1 macrophages.
abstract: Endoplasmic reticulum (ER) stress is a prominent mechanism of macrophage apoptosis in advanced atherosclerotic lesions. Recent studies from our laboratory showed that advanced atherosclerotic plaques in Apoe(-/-) mice with bone marrow deficiency of the calcium-permeable channel Transient Receptor Potential Canonical 3 (TRPC3) are characterized by reduced areas of necrosis and fewer apoptotic macrophages than animals transplanted with Trpc3(+/+) bone marrow. In vitro, proinflammatory M1 but not anti-inflammatory M2 macrophages derived from Trpc3(-/-)Apoe(-/-) animals exhibited reduced ER stress-induced apoptosis. However, whether this was due to a specific effect of TRPC3 deficiency on macrophage ER stress signaling remained to be determined. In the present work we used polarized macrophages derived from mice with macrophage-specific deficiency of TRPC3 to examine the expression level of ER stress markers and the activation status of some typical mediators of macrophage apoptosis. We found that the reduced susceptibility of TRPC3-deficient M1 macrophages to ER stress-induced apoptosis correlates with an impaired unfolded protein response (UPR), reduced mitochondrion-dependent apoptosis, and reduced activation of the proapoptotic molecules calmodulin-dependent protein kinase II and signal transducer and activator of transcription 1. Notably, none of these pathways was altered in TRPC3-deficient M2 macrophages. These findings show for the first time an obligatory requirement for a member of the TRPC family of cation channels in ER stress-induced apoptosis in macrophages, underscoring a rather selective role of the TRPC3 channel on mechanisms related to the UPR signaling in M1 macrophages.
authors.affiliation: Department of Physiology and Pharmacology and Center for Diabetes and Endocrine Research, University of Toledo Health Science Campus, Toledo, Ohio; and.
authors.forename: Sumeet
authors.initials: S
authors.lastname: Solanki
authors.affiliation: Department of Physiology and Pharmacology and Center for Diabetes and Endocrine Research, University of Toledo Health Science Campus, Toledo, Ohio; and.
authors.forename: Prabhatchandra R
authors.initials: PR
authors.lastname: Dube
authors.affiliation: Department of Physiology and Pharmacology and Center for Diabetes and Endocrine Research, University of Toledo Health Science Campus, Toledo, Ohio; and.
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Tano
authors.affiliation: Laboratory of Membrane Signaling, Department of Signal Transduction, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina.
authors.forename: Lutz
authors.initials: L
authors.lastname: Birnbaumer
authors.affiliation: Department of Physiology and Pharmacology and Center for Diabetes and Endocrine Research, University of Toledo Health Science Campus, Toledo, Ohio; and guillermo.vazquez@utoledo.edu.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Vazquez
mesh_terms: D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D002454:Cell Differentiation; D002478:Cells, Cultured; D004721:Endoplasmic Reticulum / Q000378:metabolism* / Q000473:pathology; D059865:Endoplasmic Reticulum Stress; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D050794:STAT1 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D050052:TRPC Cation Channels / Q000172:deficiency* / Q000235:genetics; D056811:Unfolded Protein Response
chemical_list: D051017:Apoptosis Regulatory Proteins; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D050052:TRPC Cation Channels; C104603:TRPC3 cation channel; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2
keywords: TRPC channels; endoplasmic reticulum stress; macrophage apoptosis