Abstract
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 H3 receptor (H3R) in myocyte regeneration and in the regulation of NLRP3 inflammasome is not known. We studied the effects of H3R 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 Nlrp3, 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 H3R had no effect on viability or apoptosis, whereas inhibition of H3R increased TNFα-induced apoptosis. Stimulation of C2C12 cells with TNFα increased Nlrp3 mRNA expression at D3 and D6. Moreover, TNFα reduced the expression of myogenesis markers MyoD1, Myogenin, and Myosin-2 at D3 and D6. H3R attenuated TNFα-induced expression of Nlrp3 and further inhibited the myogenesis marker expression; while H3R -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 H3R reduced TNFα-induced IL-1β secretion, while the H3R blockage had an opposite effect. In conclusion, the modulation of H3R activity regulates the effects of TNFα on C2C12 myocyte differentiation and TNFα-induced activation of NLRP3 inflammasome. Thus, H3R signaling may represent a novel target for limiting postinjury muscle inflammation and muscle atrophy.
Highlights
Inflammation can complicate post-injury muscle healing and slow down the regenerative repair process (Hofer et al, 2014)
By utilizing highly selective H3 receptor (H3R) agonists (Chen et al, 2015; Panula et al, 2015), and H3R blocker (Chen et al, 2015; Panula et al, 2015) we show that activation of H3R signaling mitigates the TNFα-induced NLRP3 inflammasome activation, and H3R signaling could represent a potential target for treatment in conditions involving muscle inflammation and inflammation induced muscle atrophy
Addition of H3R antagonist ciproxifan (CPX) together with TNFα had no additional effect on cell viability at the time points day 0 (D0) and D3, but further reduced the viability at time point D6 (40.3%, p < 0.05)
Summary
Inflammation can complicate post-injury muscle healing and slow down the regenerative repair process (Hofer et al, 2014). Nucleotidebinding domain and leucine-rich repeat containing family (NLR), pyrin domain containing 3 (NLRP3) inflammasome is the most widely studied inflammasome. It is activated by a myriad of factors, including exogenous pathogens and endogenous danger signals, and has been implicated in a variety of immunological (Mulay et al, 2018) and non-immunological diseases (Hughes et al, 2016). NLRP3 is associated with pro-caspase-1 via the adaptor protein ASC resulting in autoactivation of procaspase-1 into its active form. The active caspase-1 catalyzes the cleavage of the inactive precursors of interleukin 1β (pro-IL-1β) and interleukin 18 (pro-IL-18) into their active secreted forms, triggering the inflammatory storm (Man and Kanneganti, 2015). NLRP3 has been shown to be expressed in myocytes (Wei et al, 2020) and it has been implicated in the pathogenesis of inflammatory myopathies (Boursereau et al, 2018)
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