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Inflammasomes are important mediators of cyclophosphamide-induced bladder inflammation.

Publication ,  Journal Article
Hughes, FM; Vivar, NP; Kennis, JG; Pratt-Thomas, JD; Lowe, DW; Shaner, BE; Nietert, PJ; Spruill, LS; Purves, JT
Published in: Am J Physiol Renal Physiol
February 1, 2014

Bladder inflammation (cystitis) underlies numerous bladder pathologies and is elicited by a plethora of agents such as urinary tract infections, bladder outlet obstruction, chemotherapies, and catheters. Pattern recognition receptors [Toll-like receptors (TLRs) and Nod-like receptors (NLRs)] that recognize pathogen- and/or damage-associated molecular patterns (PAMPs and/or DAMPs, respectively) are key components of the innate immune system that coordinates the production (TLRs) and maturation (NLRs) of proinflammatory IL-1β. Despite multiple studies of TLRs in the bladder, none have investigated NLRs beyond one small survey. We now demonstrate that NLRP3 and NLRC4, and their binding partners apoptosis-associated speck-like protein containing a COOH-terminal caspase recruitment domain (ASC) and NLR family apoptosis inhibitory protein (NAIP), are expressed in the bladder and localized predominantly to the urothelia. Activated NLRs form inflammasomes that activate caspase-1. Placement of a NLRP3- or NLRC4-activating PAMP or NLRP3-activating DAMPs into the lumen of the bladder stimulated caspase-1 activity. To investigate inflammasomes in vivo, we induced cystitis with cyclophosphamide (CP, 150 mg/kg ip) in the presence or absence of the inflammasome inhibitor glyburide. Glyburide completely blocked CP-induced activation of caspase-1 and the production of IL-1β at 4 h. At 24 h, glyburide reduced two markers of inflammation by 30-50% and reversed much of the inflammatory morphology. Furthermore, glyburide reversed changes in bladder physiology (cystometry) induced by CP. In conclusion, NLRs/inflammasomes are present in the bladder urothelia and respond to DAMPs and PAMPs, whereas NLRP3 inhibition blocks bladder dysfunction in the CP model. The coordinated response of NLRs and TLRs in the urothelia represents a first-line innate defense that may provide an important target for pharmacological intervention.

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Published In

Am J Physiol Renal Physiol

DOI

EISSN

1522-1466

Publication Date

February 1, 2014

Volume

306

Issue

3

Start / End Page

F299 / F308

Location

United States

Related Subject Headings

  • Urology & Nephrology
  • Urinary Bladder
  • Toll-Like Receptors
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Cell Surface
  • Rats
  • Neuronal Apoptosis-Inhibitory Protein
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Inflammasomes
  • Immunity, Innate
 

Citation

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Hughes, F. M., Vivar, N. P., Kennis, J. G., Pratt-Thomas, J. D., Lowe, D. W., Shaner, B. E., … Purves, J. T. (2014). Inflammasomes are important mediators of cyclophosphamide-induced bladder inflammation. Am J Physiol Renal Physiol, 306(3), F299–F308. https://doi.org/10.1152/ajprenal.00297.2013
Hughes, Francis M., Nivardo P. Vivar, James G. Kennis, Jeffery D. Pratt-Thomas, Danielle W. Lowe, Brooke E. Shaner, Paul J. Nietert, Laura S. Spruill, and J Todd Purves. “Inflammasomes are important mediators of cyclophosphamide-induced bladder inflammation.Am J Physiol Renal Physiol 306, no. 3 (February 1, 2014): F299–308. https://doi.org/10.1152/ajprenal.00297.2013.
Hughes FM, Vivar NP, Kennis JG, Pratt-Thomas JD, Lowe DW, Shaner BE, et al. Inflammasomes are important mediators of cyclophosphamide-induced bladder inflammation. Am J Physiol Renal Physiol. 2014 Feb 1;306(3):F299–308.
Hughes, Francis M., et al. “Inflammasomes are important mediators of cyclophosphamide-induced bladder inflammation.Am J Physiol Renal Physiol, vol. 306, no. 3, Feb. 2014, pp. F299–308. Pubmed, doi:10.1152/ajprenal.00297.2013.
Hughes FM, Vivar NP, Kennis JG, Pratt-Thomas JD, Lowe DW, Shaner BE, Nietert PJ, Spruill LS, Purves JT. Inflammasomes are important mediators of cyclophosphamide-induced bladder inflammation. Am J Physiol Renal Physiol. 2014 Feb 1;306(3):F299–F308.

Published In

Am J Physiol Renal Physiol

DOI

EISSN

1522-1466

Publication Date

February 1, 2014

Volume

306

Issue

3

Start / End Page

F299 / F308

Location

United States

Related Subject Headings

  • Urology & Nephrology
  • Urinary Bladder
  • Toll-Like Receptors
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Cell Surface
  • Rats
  • Neuronal Apoptosis-Inhibitory Protein
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Inflammasomes
  • Immunity, Innate