AUTHOR=Chen Yan , Ma Yuan , Feng Jin Jin , Wang Yi He , Li Tian Fang , Nurmi Katariina , Eklund Kari K. , Wen Jian Guo 

TITLE=Histamine H3 Receptor Signaling Regulates the NLRP3 Inflammasome Activation in C2C12 Myocyte During Myogenic Differentiation

JOURNAL=Frontiers in Pharmacology

VOLUME=12

YEAR=2021

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2021.599393

DOI=10.3389/fphar.2021.599393

ISSN=1663-9812

ABSTRACT=<p>NLRP3 inflammasome has been implicated in impaired post-injury muscle healing and in muscle atrophy. Histamine receptors play an important role in inflammation, but the role of histamine H<sub>3</sub> receptor (H<sub>3</sub>R) in myocyte regeneration and in the regulation of NLRP3 inflammasome is not known. We studied the effects of H<sub>3</sub>R signaling on C2C12 myocyte viability, apoptosis, and tumor necrosis factor alpha (TNFα)-induced NLRP3 inflammasome activation during striated myogenic differentiation at three time points (days 0, 3, and 6). Expression of <italic>Nlrp3</italic>, interleukin-1β (IL-1β), and myogenesis markers were determined. TNFα reduced overall viability of C2C12 cells, and exposure to TNFα induced apoptosis of cells at D6. Activation of H<sub>3</sub>R had no effect on viability or apoptosis, whereas inhibition of H<sub>3</sub>R increased TNFα-induced apoptosis. Stimulation of C2C12 cells with TNFα increased <italic>Nlrp3</italic> mRNA expression at D3 and D6. Moreover, TNFα reduced the expression of myogenesis markers MyoD1, Myogenin, and Myosin-2 at D3 and D6. H<sub>3</sub>R attenuated TNFα-induced expression of <italic>Nlrp3</italic> and further inhibited the myogenesis marker expression; while H<sub>3</sub>R -blockage enhanced the proinflammatory effects of TNFα and increased the myogenesis marker expression. TNFα-induced secretion of mature IL-1β was dependent on the activation of the NLRP3 inflammasome, as shown by the reduced secretion of mature IL-1β upon treatment of the cells with the small molecule inhibitor of the NLRP3 inflammasome (MCC950). The activation of H<sub>3</sub>R reduced TNFα-induced IL-1β secretion, while the H<sub>3</sub>R blockage had an opposite effect. In conclusion, the modulation of H<sub>3</sub>R activity regulates the effects of TNFα on C2C12 myocyte differentiation and TNFα-induced activation of NLRP3 inflammasome. Thus, H<sub>3</sub>R signaling may represent a novel target for limiting postinjury muscle inflammation and muscle atrophy.</p>