Inflammation and pyroptosis mediate muscle expansion in an interleukin-1β (IL-1β)-dependent manner

Subhash Haldar, Christopher Dru, Diptiman Choudhury, Rajeev Mishra, Ana Fernandez, Shea Biond, Zhenqiu Li, Kenichi Shimada, Moshe Arditi, Neil A. Bhowmick

Research output: Contribution to journalArticle

20 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)6574-6583
Number of pages10
JournalJournal of Biological Chemistry
Volume290
Issue number10
DOIs
StatePublished - Mar 6 2015

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Interleukin-1
Muscle
Urinary Bladder
Inflammation
DNA Damage
Muscles
Cyclophosphamide
DNA
Interleukin 1 Receptor Antagonist Protein
Caspase 1
DNA Methylation
Acrolein
Hypertrophy
Hyperplasia
Cell death
Conditioned Culture Medium
Metabolites
Neutralizing Antibodies
Titration
Protein Array Analysis

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Haldar, S., Dru, C., Choudhury, D., Mishra, R., Fernandez, A., Biond, S., ... Bhowmick, N. A. (2015). Inflammation and pyroptosis mediate muscle expansion in an interleukin-1β (IL-1β)-dependent manner. Journal of Biological Chemistry, 290(10), 6574-6583. https://doi.org/10.1074/jbc.M114.617886
Haldar, Subhash ; Dru, Christopher ; Choudhury, Diptiman ; Mishra, Rajeev ; Fernandez, Ana ; Biond, Shea ; Li, Zhenqiu ; Shimada, Kenichi ; Arditi, Moshe ; Bhowmick, Neil A. / Inflammation and pyroptosis mediate muscle expansion in an interleukin-1β (IL-1β)-dependent manner. In: Journal of Biological Chemistry. 2015 ; Vol. 290, No. 10. pp. 6574-6583.
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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.",
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Haldar, S, Dru, C, Choudhury, D, Mishra, R, Fernandez, A, Biond, S, Li, Z, Shimada, K, Arditi, M & Bhowmick, NA 2015, 'Inflammation and pyroptosis mediate muscle expansion in an interleukin-1β (IL-1β)-dependent manner', Journal of Biological Chemistry, vol. 290, no. 10, pp. 6574-6583. https://doi.org/10.1074/jbc.M114.617886

Inflammation and pyroptosis mediate muscle expansion in an interleukin-1β (IL-1β)-dependent manner. / Haldar, Subhash; Dru, Christopher; Choudhury, Diptiman; Mishra, Rajeev; Fernandez, Ana; Biond, Shea; Li, Zhenqiu; Shimada, Kenichi; Arditi, Moshe; Bhowmick, Neil A.

In: Journal of Biological Chemistry, Vol. 290, No. 10, 06.03.2015, p. 6574-6583.

Research output: Contribution to journalArticle

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T1 - Inflammation and pyroptosis mediate muscle expansion in an interleukin-1β (IL-1β)-dependent manner

AU - Haldar, Subhash

AU - Dru, Christopher

AU - Choudhury, Diptiman

AU - Mishra, Rajeev

AU - Fernandez, Ana

AU - Biond, Shea

AU - Li, Zhenqiu

AU - Shimada, Kenichi

AU - Arditi, Moshe

AU - Bhowmick, Neil A.

PY - 2015/3/6

Y1 - 2015/3/6

N2 - 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.

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