Inflammasomes are important mediators of cyclophosphamide-induced bladder inflammation
Inflammasomes are important mediators of cyclophosphamide-induced bladder inflammation
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DOI：
10.1152/ajprenal.00297.2013
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发表时间：
2014-02-01
影响因子：
4.2
通讯作者：
Purves, J. Todd
中科院分区：
文献类型：
--
作者：
Hughes, Francis M., Jr.;Vivar, Nivardo P.;Purves, J. Todd
膀胱炎症（膀胱炎）是许多膀胱病理的基础，并由多种药物引起，如尿路感染、膀胱出口梗阻、化疗和导尿管。识别病原体和/或损伤相关分子模式（分别为PAMP和/或DAMP）的模式识别受体[Toll样受体（TLR）和Nod样受体（NLR）]是协调促炎性IL-1 β的产生（TLR）和成熟（NLR）的先天免疫系统的关键组分。尽管对膀胱中TLR进行了多项研究，但没有一项研究超过一项小型调查。我们现在证明，NLRP 3和NLRC 4，以及它们的结合伙伴膀胱移行相关的斑点样蛋白含有一个COOH-末端半胱天冬酶募集结构域（ASC）和NLR家族细胞凋亡抑制蛋白（NAIP），在膀胱中表达，并主要定位于尿路上皮。活化的NLR形成炎性体，其活化半胱天冬酶-1。将NLRP 3-或NLRC 4-活化PAMP或NLRP 3-活化DAMP置于膀胱腔中刺激半胱天冬酶-1活性。为了研究体内炎性小体，我们在存在或不存在炎性小体抑制剂格列本脲的情况下用环磷酰胺（CP，150 mg/kg ip）诱导膀胱炎。格列本脲在4 h完全阻断CP诱导的caspase-1活化和IL-1 β的产生。在24小时，格列本脲减少了30-50%的两个炎症标志物，并逆转了许多炎症形态。此外，格列本脲逆转了CP诱导的膀胱生理学（膀胱测压）变化。总之，NLR/炎性小体存在于膀胱尿路上皮中并对DAMP和PAMP产生应答，而NLRP 3抑制阻断CP模型中的膀胱功能障碍。尿路上皮中NLR和TLR的协调反应代表了一线先天防御，可能为药物干预提供重要靶点。
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.