TRPV4 attenuates M1 polarization and subsequent NASH progression by stalling CYP2E1-mediated redox toxicity via eNOS
| Autor: | Ratanesh K Seth, Varun Chandrashekaran, Diptadip Dattaroy, Firas Alhasson, Mitzi Nagarkatti, Prakash Nagarkatti, Anna Mae Diehl, Wolfgang Liedtke, Saurabh Chatterjee |
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| Rok vydání: | 2017 |
| Předmět: | |
| Zdroj: | The Journal of Immunology. 198:197.13-197.13 |
| ISSN: | 1550-6606 0022-1767 |
| Popis: | M1 macrophage polarization in nonalcoholic steatohepatitis (NASH) liver has been impacted by several exogenous or endogenous factors including inflammatory stimuli, oxidative stress, and cytokines. In absence of an active endogenous defense mechanism, the M1 polarization bias potentiates NASH progression by intensified inflammation and intermittent fibrosis in the rodent model of liver injury. We introduce an endogenous defense mechanism in the liver that is mediated by TRPV4, a transient receptor potential calcium-permeable ion channel that responds to the cytotoxic liver environment and negatively regulates CYP2E1. We hypothesized that CYP2E1-mediated oxidative stress causes M1 polarization in experimental NASH and active TRPV4 inhibits CYP2E1 mediated inflammation with concomitant attenuation of M1 polarization. Since CYP2E1 takes center stage in redox toxicity we use a toxin model of NASH which uses pyrazole, a ligand and a substrate of CYP2E1 for inducing liver injury with NASH-like phenotype. Using both cyp2e1−/− and trpv4−/− mice, we show that in the absence of active TRPV4, CYP2E1 induced oxidative stress causes M1 polarization bias, that includes a significant increase in IL-1β, IL-12, IL-6 and IL-23 while CYP2E1 null or diallyl sulfide treated mice prevent it. Recently, we discovered that the TRPV4 modulates eNOS activation and nitric oxide release from Kupffer cell during an early stage of liver injury. Based on the adaptive NO increase in trpv4+/+ mice, NO donor administration in trpv4−/− mice abrogated CYP2E1-induced oxidative stress, M1 polarization, and NASH progression. Thus, a novel endogenous defense molecule TRPV4 can be a promising immunotherapeutic approach against chronic liver injury. |
| Databáze: | OpenAIRE |
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