Transient Receptor Potential Channel 1 Deficiency Impairs Host Defense and Proinflammatory Responses to Bacterial Infection by Regulating Protein Kinase Cα Signaling

Abstract

dTransient 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 C␥ (PLC-␥), TRPC1 mediated Ca 2؉ entry and triggered protein kinase C␣ (PKC␣) activity to facilitate nuclear translocation of NF-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␣ signaling circuit. P seudomonas aeruginosa and Klebsiella pneumoniae are opportunistic Gram-negative bacteria that infect a broad range of individuals, particularly immunocompromised people, causing high morbidity and mortality. These bacteria are increasingly becoming resistant to almost all the conventional antibiotics and remain major health threats (1, 2). Better understanding of the mechanism of host-pathogen interaction may facilitate the development of novel approaches to treat these infections. A number of studies have thus far focused on the pathogenesis of P. aeruginosa and K. pneumoniae in airway infectious diseases and have identified some critical innate immunity regulators for early-stage host defense (3-5).Members of the transient receptor potential channel (TRPC) and Orai families have been suggested as mediators of Ca 2ϩ entry channels in nonexcitable cells (6). Activation of the phospholipase C (PLC) signaling pathway generates inositol trisphosphate (IP 3 ) and diacylglycerol (DAG), which initiates Ca 2ϩ release from the endoplasmic reticulum (ER) stores followed by the activation of Ca 2ϩ entry channels that increase cytosolic Ca 2ϩ levels (7, 8). Ca 2ϩ entry through receptor-mediated channels is essential for regulating cellular functions, and TRPC1, which functions as a nonselective cation channel in many cell types, has been shown to be important in Ca 2ϩ entry that is initiated by store depletion (7, 9). In particular, TRPC1 is reportedly associated with cell proliferation, cell migration, enzyme and fluid secretion, normal metabolism in various organ systems, and cancer metastasis (6, 10, 11). TRPC1 could also form a heteromultimer with Orai1 and stromal interaction molecule 1 (STIM1), which are e...

Phospholipase C‐γ2 promotes intracellular survival of mycobacteria

“…Macrophage-Mtb interactions reprogram various cellular, biochemical, and signaling events both in the host as well as the pathogen. 22 These reports suggest an important role of PLC signaling during bacterial interaction with host cells. 20 PLC signalling is involved in regulation of several cellular activities due to its ability to control the cellular levels of DAG and IP3.…”

TRPC1 intensifies house dust mite–induced airway remodeling by facilitating epithelial‐to‐mesenchymal transition and STAT3/NF‐κB signaling

“…Our previous studies have shown that silencing TRPC1 suppresses the JNK/NF-kB pathway during Gramnegative bacterial infection (19). However, TRPC1 function and its downstream signaling pathways have not been studied in HDM-induced allergic models.…”

The role of transient receptor potential channels in joint diseases

“…· decreased endothelial transmigration of neutrophils · decreased inflammatory response and ineffective bacterial clearance · no pulmonary hypertension response to chronic hypoxia and reduced vascular muscularisation Lindemann et al, 2015;Malczyk et al, 2013;Zhou et al, 2015 …”

“…· reduced secretion of CCL2 (Sun et al, 2015) TRPML3 -/-· unknown www.ecmjournal.org been shown that ECM changes and hyperalgesia may correlate with dysregulation of TRP channels, suggesting that TRP channels are involved in sensing and regulating inflammation, mechanical and osmotic stress as well as pain in joints (Gavenis et al, 2009). Current knowledge on TRP channel expression and activity in nociceptors, chondrocytes and IVD cells is summarised below and in Fig.…”