title: Inflammation and pyroptosis mediate muscle expansion in an interleukin-1β (IL-1β)-dependent manner.
abstract: 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 cyclophosphamide activated caspase 1 through the formation of the NLRP3 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 NLRP3 expression was up-regulated in human chronic bladder inflammatory tissues. The epigenetic silencing of DNA damage repair gene, Ogg1, could be reversed by the use of demethylating agents. In mice, demethylating agents reversed cyclophosphamide-induced bladder inflammation and detrusor expansion. The transgenic knock-out of Ogg1 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-1β 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-1β secretory phenotype. A protein array analysis identified IGF1 to be downstream of IL-1β signaling. IL-1β-induced detrusor proliferation and hypertrophy could be reversed with the use of Anakinra as well as an IGF1 neutralizing antibody. IL-1β antagonists in current clinical practice can exploit the revealed mechanism for DNA damage-mediated muscular expansion.
authors.affiliation: From the Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California 90048.
authors.forename: Subhash
authors.initials: S
authors.lastname: Haldar
authors.affiliation: From the Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California 90048.
authors.forename: Christopher
authors.initials: C
authors.lastname: Dru
authors.affiliation: From the Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California 90048, Greater Los Angeles Veterans Administration, Los Angeles, California, and.
authors.forename: Diptiman
authors.initials: D
authors.lastname: Choudhury
authors.affiliation: From the Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California 90048, bhowmickn@cshs.org.
authors.forename: Rajeev
authors.initials: R
authors.lastname: Mishra
authors.affiliation: From the Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California 90048, Greater Los Angeles Veterans Administration, Los Angeles, California, and.
authors.forename: Ana
authors.initials: A
authors.lastname: Fernandez
authors.affiliation: From the Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California 90048, Greater Los Angeles Veterans Administration, Los Angeles, California, and.
authors.forename: Shea
authors.initials: S
authors.lastname: Biondi
authors.affiliation: From the Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California 90048.
authors.forename: Zhenqiu
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Pediatrics, Cedars-Sinai Medical Center, Los Angeles, California.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Shimada
authors.affiliation: Department of Pediatrics, Cedars-Sinai Medical Center, Los Angeles, California.
authors.forename: Moshe
authors.initials: M
authors.lastname: Arditi
authors.affiliation: From the Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California 90048, Greater Los Angeles Veterans Administration, Los Angeles, California, and bhowmickn@cshs.org.
authors.forename: Neil A
authors.initials: NA
authors.lastname: Bhowmick
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D020170:Caspase 1 / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects; D045647:DNA Glycosylases / Q000378:metabolism; D006801:Humans; D006965:Hyperplasia / Q000378:metabolism* / Q000473:pathology; D007249:Inflammation / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism*; D053590:Interleukin 1 Receptor Antagonist Protein / Q000494:pharmacology; D053583:Interleukin-1beta / Q000378:metabolism*; D051379:Mice; D009130:Muscle, Smooth / Q000378:metabolism / Q000473:pathology*; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D015398:Signal Transduction / Q000187:drug effects; D001743:Urinary Bladder / Q000378:metabolism / Q000473:pathology
chemical_list: D002352:Carrier Proteins; C583557:IGF1 protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D007334:Insulin-Like Growth Factor I; D045647:DNA Glycosylases; C479058:oxoguanine glycosylase 1, human; D020170:Caspase 1
keywords: 8-Oxoguanine Glycosylase (OGG1); Bladder Inflammation; Caspase 1 (CASP1); Cell Death; DNA Damage; Fibroblast; Hyperplasia; Hypertrophy; Insulin-like Growth Factor (IGF); Pyroptosis