title: Transient Receptor Potential Channel 1 Deficiency Impairs Host Defense and Proinflammatory Responses to Bacterial Infection by Regulating Protein Kinase Cα Signaling.
abstract: Transient receptor potential channel 1 (TRPC1) is a nonselective cation channel that is required for Ca(2+) homeostasis necessary for cellular functions. However, whether TRPC1 is involved in infectious disease remains unknown. Here, we report a novel function for TRPC1 in host defense against Gram-negative bacteria. TRPC1(-/-) mice exhibited decreased survival, severe lung injury, and systemic bacterial dissemination upon infection. Furthermore, silencing of TRPC1 showed decreased Ca(2+) entry, reduced proinflammatory cytokines, and lowered bacterial clearance. Importantly, TRPC1 functioned as an endogenous Ca(2+) entry channel critical for proinflammatory cytokine production in both alveolar macrophages and epithelial cells. We further identified that bacterium-mediated activation of TRPC1 was dependent on Toll-like receptor 4 (TLR4), which induced endoplasmic reticulum (ER) store depletion. After activation of phospholipase Cγ (PLC-γ), TRPC1 mediated Ca(2+) entry and triggered protein kinase Cα (PKCα) activity to facilitate nuclear translocation of NF-κB/Jun N-terminal protein kinase (JNK) and augment the proinflammatory response, leading to tissue damage and eventually mortality. These findings reveal that TRPC1 is required for host defense against bacterial infections through the TLR4-TRPC1-PKCα signaling circuit.
authors.affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, China Department of Basic Sciences, University of North Dakota, Grand Forks, North Dakota, USA.
authors.forename: Xikun
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Department of Basic Sciences, University of North Dakota, Grand Forks, North Dakota, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Ye
authors.affiliation: Department of Basic Sciences, University of North Dakota, Grand Forks, North Dakota, USA.
authors.forename: Yuyang
authors.initials: Y
authors.lastname: Sun
authors.affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, China Department of Basic Sciences, University of North Dakota, Grand Forks, North Dakota, USA.
authors.forename: Xuefeng
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Basic Sciences, University of North Dakota, Grand Forks, North Dakota, USA.
authors.forename: Wenxue
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Basic Sciences, University of North Dakota, Grand Forks, North Dakota, USA.
authors.forename: Breanna
authors.initials: B
authors.lastname: Privratsky
authors.affiliation: Department of Basic Sciences, University of North Dakota, Grand Forks, North Dakota, USA.
authors.forename: Shirui
authors.initials: S
authors.lastname: Tan
authors.affiliation: Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, China.
authors.forename: Zongguang
authors.initials: Z
authors.lastname: Zhou
authors.affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, China.
authors.forename: Canhua
authors.initials: C
authors.lastname: Huang
authors.affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, China.
authors.forename: Yu-Quan
authors.initials: YQ
authors.lastname: Wei
authors.affiliation: Laboratory of Neuroscience, NIEHS, NIH, Research Triangle Park, North Carolina, USA.
authors.forename: Lutz
authors.initials: L
authors.lastname: Birnbaumer
authors.affiliation: Department of Basic Sciences, University of North Dakota, Grand Forks, North Dakota, USA brij.singh@med.und.edu min.wu@med.und.edu.
authors.forename: Brij B
authors.initials: BB
authors.lastname: Singh
authors.affiliation: Department of Basic Sciences, University of North Dakota, Grand Forks, North Dakota, USA brij.singh@med.und.edu min.wu@med.und.edu.
authors.forename: Min
authors.initials: M
authors.lastname: Wu
mesh_terms: D000818:Animals; D002118:Calcium / Q000276:immunology; D002478:Cells, Cultured; D055786:Gene Knockout Techniques; D008168:Lung / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D055370:Lung Injury / Q000209:etiology / Q000235:genetics* / Q000276:immunology / Q000382:microbiology*; D020935:MAP Kinase Signaling System; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000276:immunology; D051571:Protein Kinase C-alpha / Q000276:immunology*; D011552:Pseudomonas Infections / Q000150:complications* / Q000235:genetics* / Q000276:immunology; D011550:Pseudomonas aeruginosa / Q000276:immunology*; D015398:Signal Transduction; D050052:TRPC Cation Channels / Q000235:genetics* / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000276:immunology
chemical_list: D016328:NF-kappa B; D050052:TRPC Cation Channels; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; C096351:transient receptor potential cation channel, subfamily C, member 1; D051571:Protein Kinase C-alpha; D002118:Calcium