Journal
MOLECULAR AND CELLULAR BIOLOGY
Volume 35, Issue 16, Pages 2729-2739Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/MCB.00256-15
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Funding
- FAMRI [103007]
- National Natural Science Foundation of China [81202324]
- China Postdoctoral Science Foundation [2014T70873]
- NIH [Z01-ES101864]
- [NIH P20 RR017699]
- [NIH R01 AI109317-01A1]
- [AI101973-01]
- [AI097532-01A1]
- [R01 DE017102]
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Transient receptor potential channel 1 (TRPC1) is a nonselective cation channel that is required for Ca2+ 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 Ca2+ entry, reduced proinflammatory cytokines, and lowered bacterial clearance. Importantly, TRPC1 functioned as an endogenous Ca2+ 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 C gamma (PLC-gamma), TRPC1 mediated Ca2+ entry and triggered protein kinase C alpha (PKC alpha) activity to facilitate nuclear translocation of NF-kappa B/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-PKC alpha signaling circuit.
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