Role Of Transient Receptor Potential Vanilloid 1 Research Articles

Schizonepeta tenuifolia Briq-Saposhnikovia divaricata decoction alleviates atopic dermatitis via downregulating macrophage TRPV1.

Schizonepeta tenuifolia -Saposhnikovia divaricata (Jingjie-Fangfeng, JF) has been used for years to treat allergic inflammatory skin diseases like atopic dermatitis, but the specific effects and mechanisms of JF are still unclear. We aim to investigate the therapeutic effect and mechanism of JF in MC903-induced atopic dermatitis-like model. JF decoction was subjected to rigorous HPLC and GC analysis. The JF decoction was then freshly prepared and administered to MC903-induced atopic dermatitis -like mice models to investigate its therapeutic effects. Our evaluation focused on several markers of inflammation including the TEWL index, ear thickness, swelling, and specific inflammation indicators such as TSLP, IL33, IgE, and immune cell presence at the lesion sites. We measured Transient Receptor Potential Vanilloid 1 (TRPV1) expression levels through immunofluorescent staining in skin tissue from both atopic dermatitis patients and the MC903-treated mice. Furthermore, TRPV1 expression and macrophage activation markers were measured in LPS/IFN-γ-stimulated Raw264.7 and THP-1 cell models in vitro. Additionally, we developed cell lines that overexpress TRPV1 and investigated how JF treatment affects NF-κB p65 phosphorylation in these cells to understand better the role of TRPV1 in atopic dermatitis. The JF decoction met the standards outlined in the Chinese pharmacopeia. The JF decoction significantly alleviated inflammatory skin symptoms and helped restore skin barrier function. Additionally, it reduced the levels of IgE and pro-inflammatory cytokines TSLP, IL-33, and IL-4. There was also a noticeable decrease in mast cell infiltration and degranulation. Notably, JF decoction reduced infiltrated macrophages with limited affection on T cell infiltration. It also decreased F4/80+/TRPV1+ cells in atopic dermatitis mice and TRPV1 expression in LPS/IFNγ-stimulated microphages. Additionally, we observed that CD68+/TRPV1+ cells increased in human atopic dermatitis tissue. Further studies showed that JF water extract (JF-WE) suppressed TRPV1 expression in macrophages, potentially by affecting NF-κB p65 phosphorylation rather than the JAK-STAT6 pathway. This study offers initial evidence of the effectiveness of JF-WE in suppressing inflammation in atopic dermatitis. The therapeutic effect might stems from its ability to downregulate TRPV1 expression and subsequent NF-κB p65 phosphorylation in macrophages.

The role of TRPV4 in programmed cell deaths.

Programmed cell death is a major life activity of both normal development and disease. Necroptosis is early recognized as a caspase-independent form of programmed cell death followed obviously inflammation. Apoptosis is a gradually recognized mode of cell death that is characterized by a special morphological changes and unique caspase-dependent biological process. Ferroptosis, pyroptosis and autophagy are recently identified non-apoptotic regulated cell death that each has its own characteristics. The transient receptor potential vanilloid 4 (TRPV4) is a kind of nonselective calcium-permeable cation channel, which is received more and more attention in biology studies. It is widely expressed in human tissues and mainly located on the membrane of cells. Several researchers have identified that the influx Ca2+ from TRPV4 acts as a key role in the loss of cells by apoptosis, ferroptosis, necroptosis, pyroptosis and autophagy via mediating endoplasmic reticulum (ER) stress, oxidative stress and inflammation. This effect is bad for the normal function of organs on the one hand, on the other hand, it is benefit for anticancer activities. In this review, we will summarize the current discovery on the role and impact of TRPV4 in these programmed cell death pathological mechanisms to provide a new prospect of gene therapeutic target of related diseases.

Hypothermia Attenuates Neurotoxic Microglial Activation via TRPV4.

Therapeutic hypothermia (TH) provides neuroprotection. However, the cellular mechanisms underlying the neuroprotective effects of TH are not fully elucidated. Regulation of microglial activation has the potential to treat a variety of nervous system diseases. Transient receptor potential vanilloid 4 (TRPV4), a nonselective cation channel, is activated by temperature stimulus at 27-35°C. Although it is speculated that TRPV4 is associated with the neuroprotective mechanisms of TH, the role of TRPV4 in the neuroprotective effects of TH is not well understood. In the present study, we investigated whether hypothermia attenuates microglial activation via TRPV4 channels. Cultured microglia were incubated under normothermic (37°C) or hypothermic (33.5°C) conditions following lipopolysaccharide (LPS) stimulation. Hypothermic conditions suppressed the expression of pro-inflammatory cytokines, inducible nitric oxide synthase, and the number of phagocytic microglia. AMP-activated protein kinase (AMPK)-NF-κB signaling was inhibited under hypothermic conditions. Furthermore, hypothermia reduced neuronal damage induced by LPS-treated microglial cells. Treatment with TRPV4 antagonist in normothermic culture replicated the suppressive effects of hypothermia on microglial activation and microglia-induced neuronal damage. In contrast, treatment with a TRPV4 agonist in hypothermic culture reversed the suppressive effect of hypothermia. These findings suggest that TH suppresses microglial activation and microglia-induced neuronal damage via the TRPV4-AMPK-NF-κB pathway. Although more validation is needed to consider differences according to age, sex, and specific central nervous system regions, our findings may offer a novel therapeutic approach to complement TH.

TRPV4 blockade alleviates endoplasmic reticulum stress mediated apoptosis in hypoxia–induced cardiomyocyte injury

BackgroundHypoxia-induced myocardial injury remains to be a huge health issue worldwide. Transient receptor potential vanilloid 4 (TRPV4) is a high-flux Ca2+ channel that is involved in numerous cardiovascular diseases. However, the role of TRPV4 in myocardial hypoxic injury remains unclear. Accordingly, this study aimed to investigate the antiapoptotic activity of TRPV4 inhibition and elucidate the underlying mechanisms in myocardial hypoxic injury. MethodsThe ability of TRPV4 to modulate the endoplasmic reticulum stress (ERS) and apoptosis was assessed in vitro through the administration of the TRPV4 antagonist HC-067047 or the agonist GSK1016790A. Additionally, intracellular Ca2+ concentration was measured by Fluo-4 AM. ResultsTRPV4 expression was significantly upregulated in hypoxic H9c2 cells compared with that in normoxic cardiomyocytes, accompanied with increased intracellular Ca2+ levels. Conversely, TRPV4 inhibition alleviated ERS in hypoxic H9c2 cells and prevented apoptosis, whereas TRPV4 agonist exacerbated such events. Furthermore, H9c2 cell apoptosis was attenuated with the administration of 4-PBA, an ERS inhibitor. ConclusionTRPV4 inhibition alleviates hypoxia-induced H9c2 cell apoptosis by mitigating ERS.

The role of TRPV4 in the regulation of retinal ganglion cells apoptosis in rat and mouse

Retinal ganglion cell (RGC) damages are common in glaucoma, causing atrophy of the optic papilla, visual field damage, and visual loss. Transient receptor potential vanilloid 4 (TRPV4) is significantly expressed in the eyeball and is sensitive to mechanical and osmotic pressure. However, the specific role and mechanism of TRPV4 in glaucoma and RGC progression remain unclear. TRPV4 expression was detected in RGCs under different pressure culture conditions. We also explored the pressure effect on TRPV4 expression and the role and mechanism behind the functional regulation of RGCs. Immunofluorescence staining, western blotting, and TUNEL were utilized in this study. Our results established that TRPV4 was expressed in RGCs. TRPV4 expression was decreased at 40 mmHg and 60 mmHg, and the expression of BAX at 40 mmHg, 60 mmHg. Additionally, the expression of caspase 9 protein increased at 40 mmHg with the pressure increase compared with the conventional culture group. TUNEL staining revealed that the apoptosis rate of RGCs was elevated at 40 mmHg and 60 mmHg, compared with the traditional culture group. Therefore, the expression of BAX and caspase 9 increased, along with the apoptosis rate of RGCs compared with the control group. However, after TRPV4 antagonist treatment, the expression of BAX and caspase 9 decreased, and the apoptosis rate of RGCs decreased. Thus, TRPV4 may affect the mitochondrial apoptosis pathway, such as BAX and caspase 9, leading to the apoptosis of RGCs. The antagonists of TRPV4 could provide a new idea for clinically treating acute glaucoma.

Expression of the Transient Receptor Potential Vanilloid 1 ion channel in the supramammillary nucleus and the antidepressant effects of its antagonist AMG9810 in mice

The Transient Receptor Potential Vanilloid 1 (TRPV1) non-selective cation channel predominantly expressed in primary sensory neurons of the dorsal root and trigeminal ganglia mediates pain and neurogenic inflammation. TRPV1 mRNA and immunoreactivity were described in the central nervous system (CNS), but its precise expression pattern and function have not been clarified. Here we investigated Trpv1 mRNA expression in the mouse brain using ultrasensitive RNAScope in situ hybridization. The role of TRPV1 in anxiety, depression-like behaviors and memory functions was investigated by TRPV1-deficient mice and pharmacological antagonism by AMG9810. Trpv1 mRNA is selectively expressed in the supramammillary nucleus (SuM) co-localized with Vglut2 mRNA, but not with tyrosine hydroxylase immunopositivity demonstrating its presence in glutamatergic, but not dopaminergic neurons. TRPV1-deleted mice exhibited significantly reduced anxiety in the Light-Dark box and depression-like behaviors in the Forced Swim Test, but their performance in the Elevated Plus Maze as well as their spontaneous locomotor activity, memory and learning function in the Radial Arm Maze, Y-maze and Novel Object Recognition test were not different from WTs. AMG9810 (intraperitoneal injection 50 mg/kg) induced anti-depressant, but not anxiolytic effects. It is concluded that TRPV1 in the SuM might have functional relevance in mood regulation and TRPV1 antagonism could be a novel perspective for anti-depressant drugs.

Modulation of TRPV4 protects against degeneration induced by sustained loading and promotes matrix synthesis in the intervertebral disc.

While it is well known that mechanical signals can either promote or disrupt intervertebral disc (IVD) homeostasis, the molecular mechanisms for transducing mechanical stimuli are not fully understood. The transient receptor potential vanilloid 4 (TRPV4) ion channel activated in isolated IVD cells initiates extracellular matrix (ECM) gene expression, while TRPV4 ablation reduces cytokine production in response to circumferential stretching. However, the role of TRPV4 on ECM maintenance during tissue-level mechanical loading remains unknown. Using an organ culture model, we modulated TRPV4 function over both short- (hours) and long-term (days) and evaluated the IVDs' response. Activating TRPV4 with the agonist GSK101 resulted in a Ca2+ flux propagating across the cells within the IVD. Nuclear factor (NF)-κB signaling in the IVD peaked at 6 h following TRPV4 activation that subsequently resulted in higher interleukin (IL)-6 production at 7 days. These cellular responses were concomitant with the accumulation of glycosaminoglycans and increased hydration in the nucleus pulposus that culminated in higher stiffness of the IVD. Sustained compressive loading of the IVD resulted in elevated NF-κB activity, IL-6 and vascular endothelial growth factor A (VEGFA) production, and degenerative changes to the ECM. TRPV4 inhibition using GSK205 during loading mitigated the changes in inflammatory cytokines, protected against IVD degeneration, but could not prevent ECM disorganization due to mechanical damage in the annulus fibrosus. These results indicate TRPV4 plays an important role in both short- and long-term adaptations of the IVD to mechanical loading. The modulation of TRPV4 may be a possible therapeutic for preventing load-induced IVD degeneration.

The interaction of TRPV1 and lipids: Insights into lipid metabolism.

Transient receptor potential vanilloid 1 (TRPV1), a non-selective ligand-gated cation channel with high permeability for Ca2+, has received considerable attention as potential therapeutic target for the treatment of several disorders including pain, inflammation, and hyperlipidemia. In particular, TRPV1 regulates lipid metabolism by mechanisms that are not completely understood. Interestingly, TRPV1 and lipids regulate each other in a reciprocal and complex manner. This review surveyed the recent literature dealing with the role of TRPV1 in the hyperlipidemia-associated metabolic syndrome. Besides TRPV1 structure, molecular mechanisms underlying the regulatory effect of TRPV1 on lipid metabolism such as the involvement of uncoupling proteins (UCPs), ATP-binding cassette (ABC) transporters, peroxisome proliferation-activated receptors (PPAR), sterol responsive element binding protein (SREBP), and hypoxia have been discussed. Additionally, this review extends our understanding of the lipid-dependent modulation of TRPV1 activity through affecting both the gating and the expression of TRPV1. The regulatory role of different classes of lipids such as phosphatidylinositol (PI), cholesterol, estrogen, and oleoylethanolamide (OEA), on TRPV1 has also been addressed.

Activation of TRPV1 receptor facilitates myelin repair following demyelination via the regulation of microglial function.

The transient receptor potential vanilloid 1 (TRPV1) is a non-selective cation channel that is activated by capsaicin (CAP), the main component of chili pepper. Despite studies in several neurological diseases, the role of TRPV1 in demyelinating diseases remains unknown. Herein, we reported that TRPV1 expression was increased within the corpus callosum during demyelination in a cuprizone(CPZ)-induced demyelination mouse model. TRPV1 deficiency exacerbated motor coordinative dysfunction and demyelination in CPZ-treated mice, whereas the TRPV1 agonist CAP improved the behavioral performance and facilitated remyelination. TRPV1 was predominantly expressed in Iba1+ microglia/macrophages in human brain sections of multiple sclerosis patients and mouse corpus callosum under demyelinating conditions. TRPV1 deficiency decreased microglial recruitment to the corpus callosum, with an associated increase in the accumulation of myelin debris. Conversely, the activation of TRPV1 by CAP enhanced the recruitment of microglia to the corpus callosum and potentiated myelin debris clearance. Using real-time live imaging we confirmed an increased phagocytic function of microglia following CAP treatment. In addition, the expression of the scavenger receptor CD36 was increased, and that of the glycolysis regulators Hif1a and Hk2 was decreased. We conclude that TRPV1 is an important regulator of microglial function in the context of demyelination and may serve as a promising therapeutic target for demyelinating diseases such as multiple sclerosis.

TRPV1 as an anti-ferroptotic target in osteoarthritis.

TRPV1 as an anti-ferroptotic target in osteoarthritis.

N-Oleoyl dopamine induces IL-10 via central nervous system TRPV1 and improves endotoxemia and sepsis outcomes

BackgroundThe transient receptor potential vanilloid 1 (TRPV1) participates in thermosensation and inflammatory pain, but its immunomodulatory mechanisms remain enigmatic. N-Oleoyl dopamine (OLDA), an endovanilloid and endocannabinoid, is a TRPV1 agonist that is produced in the central nervous system and the peripheral nervous system. We studied the anti-inflammatory effects and TRPV1-dependent mechanisms of OLDA in models of inflammation and sepsis.MethodsMice were challenged intratracheally or intravenously with LPS, or intratracheally with S. aureus to induce pneumonia and sepsis, and then were treated intravenously with OLDA. Endpoints included plasma cytokines, leukocyte activation marker expression, mouse sepsis scores, lung histopathology, and bacterial counts. The role of TRPV1 in the effects of OLDA was determined using Trpv1−/− mice, and mice with TRPV1 knockdown pan-neuronally, in peripheral nervous system neurons, or in myeloid cells. Circulating monocytes/macrophages were depleted using clodronate to determine their role in the anti-inflammatory effects of OLDA in endotoxemic mice. Levels of exogenous OLDA, and of endovanilloids and endocannabinoids, at baseline and in endotoxemic mice, were determined by LC–MS/MS.ResultsOLDA administration caused an early anti-inflammatory response in endotoxemic and septic mice with high serum levels of IL-10 and decreased levels of pro-inflammatory cytokines. OLDA also reduced lung injury and improved mouse sepsis scores. Blood and lung bacterial counts were comparable between OLDA- and carrier-treated mice with S. aureus pneumonia. OLDA’s effects were reversed in mice with pan-neuronal TRPV1 knockdown, but not with TRPV1 knockdown in peripheral nervous system neurons or myeloid cells. Depletion of monocytes/macrophages reversed the IL-10 upregulation by OLDA in endotoxemic mice. Brain and blood levels of endovanilloids and endocannabinoids were increased in endotoxemic mice.ConclusionsOLDA has strong anti-inflammatory actions in mice with endotoxemia or S. aureus pneumonia. Prior studies focused on the role of peripheral nervous system TRPV1 in modulating inflammation and pneumonia. Our results suggest that TRPV1-expressing central nervous system neurons also regulate inflammatory responses to endotoxemia and infection. Our study reveals a neuro-immune reflex that during acute inflammation is engaged proximally by OLDA acting on neuronal TRPV1, and through a multicellular network that requires circulating monocytes/macrophages, leads to the systemic production of IL-10.

Activation of TRPV4 stimulates transepithelial K+ secretion in rat epididymal epithelium

The maturation of sperms is dependent on the coordinated interactions between sperm and the unique epididymal luminal milieu, which is characterized by high K+ content. This study investigated the involvement of transient receptor potential vanilloid 4 (TRPV4) in the K+ secretion of epididymal epithelium. The expression level and cellular localization of TRPV4 and Ca2+-activated K+ channels (KCa) were analyzed via RT-PCR, real-time quantitative PCR, western blot and immunofluorescence. The functional role of TRPV4 was investigated using short-circuit current (ISC) and intracellular Ca2+ imaging techniques. We found a predominant expression of TRPV4 in the corpus and cauda epididymal epithelium. Activation of TRPV4 with a selective agonist, GSK1016790A, stimulated a transient decrease in the ISC of the epididymal epithelium. The ISC response was abolished by either the TRPV4 antagonists, HC067047 and RN-1734, or the removal of basolateral K+. Simultaneously, the application of GSK1016790A triggered Ca2+ influx in epididymal epithelial cells. Our data also indicated that the big conductance KCa (BK), small conductance KCa (SK) and intermediate conductance KCa (IK) were all expressed in rat epididymis. Pharmacological studies revealed that BK, but not SK and IK, mediated TRPV4-elicited transepithelial K+ secretion. Finally, we demonstrated that TRPV4 and BK were localized in the epididymal epithelium, which showed an increased expression level from caput to cauda regions of rat epididymis. This study implicates that TRPV4 plays an important role in the formation of high K+ concentration in epididymal intraluminal fluid via promoting transepithelial K+ secretion mediated by BK.

Transient receptor potential vanilloid 4 promotes the growth of non-small cell lung cancer by regulating Foxp3.

Transient receptor potential vanilloid 4 (TRPV4) participates in malignant tumor. However, the role of TRPV4 in non-small cell lung cancer (NSCLC) remains unclear. In this study, we demonstrated TRPV4 was upregulated in NSCLC tissues and NSCLC cell lines. TRPV4 level in the NSCLC patients and cell lines were detected, and its function was studied both in vivo and vitro. The level of TRPV4 showed a positive correlation with tumor size of NSCLC patients. Activation TRPV4 by agonist GSK1016790A promoted cell proliferation and decreased apoptosis in A549 cells, and these effects were enhanced when the cells have overexpressed TRPV4. Moreover, GSK1016790A induced inhibitory effects on apoptosis of A549 cells was impaired when GSK1016790A used together with TRPV4 selective antagonist HC-067047, or impaired when the cells have already downregulated TRPV4 expression by TRPV4 siRNA. In vivo study, pharmacological inhibition of TRPV4 prevented A549 cells transplanted tumor growth. It was showed Foxp3 level was significantly increased in the NSCLC tissues, and showed a positive correlation with the level of TRPV4. Deactivation of TRPV4 using TRPV4 siRNA or HC-067047 significantly reduced expression of Foxp3 in GSK1016790A treated NSCLC cells. Moreover, downregulation Foxp3 by transfection of Foxp3 siRNA significantly impaired TRPV4 induced NSCLC cells proliferations in vitro. Antitumor effects caused by TRPV4 inhibition in NSCLC might be attributed to the suppression of Foxp3 which induced subsequent cell apoptosis. Thus, pharmacological inhibition of TRPV4 may be a promising option for NSCLC treatment.

Mucin secretory action of capsaicin prevents high fat diet-induced gut barrier dysfunction in C57BL/6 mice colon.

The gut barrier - including tight junction proteins (TJPs) and mucus layers, is the first line of defense against physical, chemical or pathogenic incursions. This barrier is compromised in various health disorders. Capsaicin, a dietary agonist of Transient receptor potential vanilloid 1 (TRPV1) channel, is reported to alleviate the complications of obesity. While it is well known to improve energy expenditure and metabolism, and prevent dysbiosis, the more local effects on the host gut - particularly the gut barrier and mucus system remain elusive. To investigate the effect of capsaicin on the gut barrier and mucus production and to understand the involvement of mucus, bacteria, and TRPV1 in these phenomena, we employed a diet-induced obesity model in C57BL/6 mice, and capsaicin (2mg/kg/day p.o.) or mucin (1g/kg/day p.o.) as interventions, for 12 weeks. Parameters like weight gain, glucose homeostasis, TJPs expression, mucus staining, intestinal permeability etc were studied. 16S rDNA sequencing and in vitro Ca2+ measurement experiments were performed to explore the role of microbiota in the beneficial effects. Mucin feeding reflected several anti-obesity effects produced by capsaicin, suggesting that mucus modulation might play a crucial role in capsaicin-induced anti-obesity effects. 16S rDNA sequencing and in vitro Ca2+ measurement experiments pointed to TRPV1 modulation by bacteria besides capsaicin. Capsaicin, bacteria and the host mucus system seem to act in a cyclic cascade involving TRPV1, which can be activated by capsaicin and various bacteria. These findings provide new insight into the role of TRPV1 in maintaining a healthy gut environment.

TRPV1 alleviates osteoarthritis by inhibiting M1 macrophage polarization via CA2+/CAMKII/NRF2 signaling pathway

Purpose: To investigate the role and regulatory mechanism of transient receptor potential vanilloid 1 (TRPV1) in the M1 macrophage polarization and pathogenesis of osteoarthritis (OA). Methods: The levels of TRPV1 and macrophage markers (F4/80 and iNOS) were analyzed in the synovium of OA patients and in a rat OA model (radial transection of the medial meniscus) by immunofluorescence and immunohistochemical staining. The role of TRPV1 was examined using the rat OA model by intra-articular injection of capsaicin (CPS), a specific TRPV1 agonist. The levels of hyperplasia and cell infiltration of synovium, osteophyte formation and cartilage damage were assessed by a synovitis score, micro-CT and the Osteoarthritis Research Society International score, respectively. RAW264.7 cells were used to explore the mechanisms of M1 macrophage polarization by TRPV1. Results: TRPV1 expression and M1 macrophage infiltration were simultaneously increased in both human and rat OA synovium. More than 90% of the infiltrated M1 macrophages expressed TRPV1. The intra-articular injection of CPS significantly attenuated OA phenotypes, including joint swelling, synovitis, cartilage damage, and osteophyte formation. CPS treatment markedly reduced M1 macrophage infiltration in the synovium. TRPV1-evoked Ca2+ influx promoted the phosphorylation of calcium/calmodulin-dependent protein kinase II (CaMKII) and facilitated the nuclear localization of nuclear factor-erythroid 2-related factor 2 (Nrf2), which ultimately resulted in the inhibition of M1 macrophage polarization. Conclusions: TRPV1 attenuates the progression of OA by inhibiting M1 macrophage polarization in synovium via the Ca2+/CaMKII/Nrf2 signaling pathway. TRPV1 can be a therapeutic target for synovitis in OA

TRPV4 Plays a Role in Matrix Stiffness-Induced Macrophage Polarization.

Phenotypic polarization of macrophages is deemed essential in innate immunity and various pathophysiological conditions. We have now determined key aspects of the molecular mechanism by which mechanical cues regulate macrophage polarization. We show that Transient Receptor Potential Vanilloid 4 (TRPV4), a mechanosensitive ion channel, mediates substrate stiffness-induced macrophage polarization. Using atomic force microscopy, we showed that genetic ablation of TRPV4 function abrogated fibrosis-induced matrix stiffness generation in skin tissues. We have determined that stiffer skin tissue promotes the M1 macrophage subtype in a TRPV4-dependent manner; soft tissue does not. These findings were further validated by our in vitro results which showed that stiff matrix (50 kPa) alone increased expression of macrophage M1 markers in a TRPV4-dependent manner, and this response was further augmented by the addition of soluble factors; neither of which occurred with soft matrix (1 kPa). A direct requirement for TRPV4 in M1 macrophage polarization spectrum in response to increased stiffness was evident from results of gain-of-function assays, where reintroduction of TRPV4 significantly upregulated the expression of M1 markers in TRPV4 KO macrophages. Together, these data provide new insights regarding the role of TRPV4 in matrix stiffness-induced macrophage polarization spectrum that may be explored in tissue engineering and regenerative medicine and targeted therapeutics.

Transient stimulation of TRPV4-expressing keratinocytes promotes hair follicle regeneration in mice.

Hair follicle telogen to anagen transition results in a break in cellular quiescence of the hair follicle stem cells, which subsequently promotes hair follicle regeneration. Many critical molecules and signalling pathways are involved in hair follicle cycle progression. Transient receptor potential vanilloid 4 (TRPV4) is a polymodal sensory transducer that regulates various cutaneous functions under both normal and disease conditions. However, the role of TRPV4 in hair follicle regeneration in vivo remains incompletely understood. Using adult C57BL/6J mice, keratinocyte (K14Cre ; Trpv4f/f ) and macrophage (Cx3cr1Cre ; Trpv4f/f ) Trpv4 conditional knockout (cKO) mice, Trpv4-/- mice, we investigated the effect of a single intradermal injection of GSK1016790A, a potent and selective small molecule TRPV4 activator, on hair follicle regeneration. Chemical cues and signal molecules involved in hair follicle cycle progression were measured by immunofluorescence staining, quantitative RT-PCR and western blotting. Here, we show that a single intradermal injection of GSK1016790A is sufficient to induce telogen to anagen transition and hair follicle regeneration in mice by increasing the expression of the anagen-promoting growth factors and down-regulating the expression of growth factors that inhibit anagen. The action of GSK1016790A relies largely on the function of TRPV4 in skin and involves activation of downstream ERK signalling. Our results suggest that transient chemical activation of TRPV4 in the skin induces hair follicle regeneration in mice, which might provide an effective therapeutic strategy for the treatment of hair loss and alopecia.

The Role of TRPV4 in Regulating Innate Immune Cell Function in Lung Inflammation.

Ion channels/pumps are essential regulators of innate immune cell function. Macrophages have been increasingly recognized to have phenotypic plasticity and location-specific functions in the lung. Transient receptor potential vanilloid 4 (TRPV4) function in lung injury has been shown to be stimulus- and cell-type specific. In the current review, we discuss the importance of TRPV4 in macrophages and its role in phagocytosis and cytokine secretion in acute lung injury/acute respiratory distress syndrome (ARDS). Furthermore, TRPV4 controls a MAPK molecular switch from predominately c-Jun N-terminal kinase, JNK activation, to that of p38 activation, that mediates phagocytosis and cytokine secretion in a matrix stiffness-dependent manner. Expanding knowledge regarding the downstream mechanisms by which TRPV4 acts to tailor macrophage function in pulmonary inflammatory diseases will allow for formulation of novel therapeutics.

Transient receptor potential vanilloid4 channels as therapeutic targets in diabetes and diabetes-related complications.

With an estimated 425 million diabetes patients worldwide in 2019, type 2 diabetes has reached a pandemic proportion and represents a major unmet medical need. A key determinant of the development and progression of type 2 diabetes is pancreatic ‐cell dysfunction, including the loss of cell mass, the impairment of insulin biosynthesis and inadequate exocytosis. Recent studies have shown that transient receptor potential vanilloid 4 (TRPV4), a Ca2+‐permeable non‐selective cation channel, is involved in ‐cell replication, insulin production and secretion. TRPV4 agonists have insulinotropic activity in pancreatic ‐cell lines, but the prolonged activation of TRPV4 leads to ‐cell dysfunction and death. In addition, TRPV4 is involved in a wide variety of pathophysiological activities, and has been reported to play an important role in diabetes‐related complications, such as obesity, cardiovascular diseases, diabetic retinopathy, nephropathy and neuropathy. In a rodent type 2 diabetes model, Trpv4 agonists promote vasodilation and improve cardiovascular function, whereas Trpv4 antagonists reduce high‐fat diet‐induced obesity, insulin resistance, diabetic nephropathy, retinopathy and neuropathy. These findings raise interest in using TRPV4 as a therapeutic target for type 2 diabetes. In this review, we intend to summarize the latest findings regarding the role of TRPV4 in diabetes as well as diabetes‐related conditions, and to evaluate its potential as a therapeutic target for diabetes and diabetes‐related diseases.

Robust expression of SIRT6 inhibits pulpitis via activation of the TRPV1 channel.

Invasion of dentinal tubules and pulp tissue by pathogenic bacteria may cause infection leading to pulpitis. Sirtuin 6 (SIRT6) is a NAD-dependent protein deacetylase encoded by the SIRT6 gene. The effect of SIRT6 on lipopolysaccharide (LPS)-induced pulpitis and its mechanism of action were discussed in this study. Dental pulp cells (DPCs) were extracted from human teeth and injected with LPS to induce inflammation. The cells injected with LPS showed substantially decreased expression of SIRT6. The overexpression of SIRT6, induced by plasmid-transfection of DPCs with SIRT6 overexpressing vector, led to a marked decrease in proinflammatory cytokines (IL-6, IL-1β, and TNF-α) and deactivation of NF kappa B pathway. Additionally, dentin matrix protein-1 (DMP1), a promoter of inflammation in dental pulp tissues, was downregulated. Further investigation revealed that SIRT6 promotes ubiquitination of the transient receptor potential vanilloid 1 (TRPV1) channel, leading to its degradation and deactivation. The role of TRPV1 in the anti-inflammatory effects of SIRT6 was determined through incubation of SIRT6-expressing dental pulp stem cells (DPSCs) with capsaicin. This incubation counteracted the effect of SIRT6 on cytokines and DMP1. The injection of lentivirus-SIRT6 attenuated LPS-induced pulpitis in vivo by suppressing TRPV1 activity. Thus, SIRT6 inhibits the TRPV1 channel during LPS-induced inflammation of dental pulp. SIGNIFICANCE OF THE STUDY: This study discussed the effect of sirtuin 6 (SIRT6) on lipopolysaccharide (LPS)-induced pulpitis as well as its mechanism of action and found that SIRT6 may be a negative regulator of pulpitis. Additionally, low expression of SIRT6 and high expression of transient receptor potential vanilloid 1 (TRPV1) in LPS-treated human dental pulp cells are closely associated with proinflammatory cytokines, dentin matrix protein 1 expression, and activation of the NF-κB pathway, which indicated that TRPV1 may be a biomarker for pulpitis and the SIRT6-TRPV1-CGRP axis maybe a clinical target due to their role regulating inflammation and neuropathic pain.