Inflammation and Pyroptosis Mediate Muscle Expansion in an Interleukin-1β (IL-1β)-dependent Manner

Muscle inflammation is often associated with its expansion. Bladder smooth muscle inflammation-induced cell death is accompanied by hyperplasia and hypertrophy as the primary cause for poor bladder function. In mice, DNA damage initiated by chemotherapeutic drug cydophosphamide activated caspase 1 through the formation of the NINP3 complex resulting in detrusor hyperplasia. A cyclophosphamide metabolite, acrolein, caused global DNA methylation and accumulation of DNA damage in a mouse model of bladder inflammation and in cultured bladder muscle cells. In correlation, global DNA methylation and NLRP:3 expression was up-regulated in human chronic bladder inflammatory tissues. The epigenetic silencing of DNA damage repair gene, Oggl, could be reversed by the use of demethylating agents. In mice, demethylating agents reversed cydophosphamide-induced bladder inflammation and detrusor expansion. The transgenic knock-out olOgg1 in as few as 10% of the detrusor cells tripled the proliferation of the remaining wild type counterparts in an in vitro co-culture titration experiment. Antagonizing IL-1 beta with Anakinra, a rheumatoid arthritis therapeutic, prevented detrusor proliferation in conditioned media experiments as well as in a mouse model of bladder inflammation. Radiation treatment validated the role of DNA damage in the NLRP3-associated caspase 1-mediated IL-1 beta secretory phenotype. A protein array analysis identified IGF1 to be downstream of IL-1 beta signaling. IL-1 beta-induced detrusor proliferation and hypertrophy could be reversed with the use of Anakinra as well as an IGT1 neutralizing antibody. IL-1 beta antagonists in current clinical practice can exploit the revealed mechanism for DNA damage-mediated muscular expansion.