Inflammasomes are important mediators of cyclophosphamide-induced bladder inflammation

被引:72
作者
Hughes, Francis M., Jr. [1 ]
Vivar, Nivardo P. [1 ]
Kennis, James G. [1 ]
Pratt-Thomas, Jeffery D. [1 ]
Lowe, Danielle W. [2 ]
Shaner, Brooke E. [3 ]
Nietert, Paul J. [4 ]
Spruill, Laura S. [5 ]
Purves, J. Todd [1 ,2 ,6 ]
机构
[1] Med Univ S Carolina, Dept Urol, Charleston, SC 29425 USA
[2] Med Univ S Carolina, Dept Pediat, Charleston, SC 29425 USA
[3] Med Univ S Carolina, Dept Pharmaceut & Biomed Sci, Charleston, SC 29425 USA
[4] Med Univ S Carolina, Dept Publ Hlth Sci, Charleston, SC 29425 USA
[5] Med Univ S Carolina, Dept Pathol & Lab Med, Charleston, SC 29425 USA
[6] Med Univ S Carolina, Dept Regenerat Med & Cell Biol, Charleston, SC 29425 USA
关键词
inflammasome; bladder; inflammation; cystitis; caspase-1; MONOCYTE CHEMOATTRACTANT PROTEIN-1; INDUCED HEMORRHAGIC CYSTITIS; STEM-CELL TRANSPLANTATION; SMOOTH-MUSCLE-CELLS; TOLL-LIKE RECEPTORS; URINARY-BLADDER; IMMUNE-RESPONSES; CLINICAL-TRIAL; BK-VIRUS; EXPRESSION;
D O I
10.1152/ajprenal.00297.2013
中图分类号
Q4 [生理学];
学科分类号
071003 [生理学];
摘要
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-1 beta. 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-1 beta 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.
引用
收藏
页码:F299 / F308
页数:10
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