Lipopolysaccharide (LPS) is an essential component of the outer wall of gram-negative bacteria and can induce a strong inflammatory response in the body. Acyloxyacyl hydrolase (AOAH) is a highly conserved host lipase expressed in a variety of cells, including neutrophils, macrophages and proximal tubular epithelial cells. AOAH can inactivate LPS by selectively removing the secondary acyl chains from the lipid A moiety of gram-negative bacterial LPS, which alleviates inflammation and tissue damage, promotes the recovery from the immune tolerance and regains normal responsiveness. It plays an essential role in host defenses against infection. Moreover, AOAH has been shown invivo and invitro for a variety of enzymatic activities including phospholipase, lysophospholipase and diacylglycerol lipase. Researches increasingly show that AOAH plays a critical role in various noninfectious diseases such as allergic asthma, psoriasis, chronic pelvic pain and other autoimmune diseases and chronic inflammatory diseases in addition to infections. Besides, DING Feng Research Group, Department of Nephrology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine found that AOAH was capable of attenuating renal fibrosis via proximal renal tubular epithelial cells CD74 signaling pathway. Given the increasingly diverse role of AOAH in diseases, this article reviews its sources, structure, effects and possible mechanisms in diseases in order to provide reference for future research on its roles in diseases and new lines of investigation into disease pathogenesis and novel therapeutic targets.
WU Zhenkai, DENG Bo, PAN Yu, DING Feng. Research progress in the role and mechanism of acyloxyacyl hydrolase in diseases. Journal of Shanghai Jiao Tong University (Medical Science)[J], 2023, 43(1): 101-107 doi:10.3969/j.issn.1674-8115.2023.01.013
AOAH在肝脏感染性疾病中同样扮演重要角色［6，19］。肝、脾是清除血液中LPS的主要器官。SHAO等［6］发现，在静脉注射LPS后，相较于野生型小鼠，Aoah基因缺陷小鼠肝脏中炎症细胞浸润更加显著，肝、脾肿大也更加明显，而外源性重组AOAH可以恢复Aoah基因缺陷小鼠脱酰化LPS的能力，并且逆转由LPS引起的肝、脾肿大。此外，LIU等［19］研究发现，热休克蛋白A12A（heat shock protein family A member 12A，Hspa12a）基因敲除小鼠在LPS诱导后表现出更严重的急性肝损伤，AOAH的表达也明显减少，而过表达Aoah可以逆转在LPS诱导后由于HSPA12A缺乏所引起的肝细胞焦亡；进一步研究显示，HSPA12A通过与过氧化物酶体增殖物激活受体γ辅激活因子1α（peroxisome proliferator-activated receptor-γ coactivator-1α，PGC-1α）相互作用上调AOAH表达从而灭活LPS，进而抑制含半胱氨酸的天冬氨酸蛋白水解酶-11（caspase-11）介导的肝细胞焦亡。深入对AOAH功能与通路的研究有助于我们更好地了解肝脏感染性疾病的病理生理过程，并寻找新的治疗靶点。
AOAH不仅能灭活LPS从而减轻感染所引起的炎症损伤，还能促进机体脱离LPS诱导的免疫耐受状态，恢复正常免疫应答与抵御再次感染的能力［1］。LU等［1］在给小鼠腹腔注射小剂量LPS或磷酸盐缓冲液（phosphate buffer saline，PBS）后，在不同时间测量血浆白介素-6（interleukin-6，IL-6）、正常T细胞表达和分泌的活性调节蛋白（regulated upon activation normal T expressed and secreted，RANTES）等因子水平以评估小鼠再次应对LPS的免疫应答能力；结果显示野生型小鼠与Aoah基因缺陷小鼠应对第1次LPS刺激产生的免疫应答能力没有差异，但是Aoah基因缺陷小鼠对第2次LPS刺激产生免疫应答的时间明显延长，缺乏AOAH所致的免疫耐受延长进一步损害小鼠控制感染的能力，而过表达Aoah可以避免以上免疫耐受的延长。进一步研究发现，缺乏AOAH所致的LPS持续存在会延长巨噬细胞重编程的时间［20-21］，在此期间表现为免疫耐受，机体应对感染反应迟缓，炎症消退减慢，死亡率升高［21］。因此，AOAH对于机体恢复免疫稳态，产生正常免疫应答能力抵御感染至关重要。
AOAH可能通过发挥其磷脂酶A2（phospholipase A2，PLA2）活性参与银屑病的发病过程［25-26］。膜磷脂与磷脂酰胆碱经过PLA2水解后的产物（如溶血磷脂酰胆碱）能被白细胞分化抗原1a（cluster of differentiation 1a，CD1a）自身反应性T细胞识别。SINGH等［25］发现，由AOAH的PLA2酶活性所介导产生的代谢产物促进了CD1a自身反应性T细胞的激活，并导致IFN-γ和IL-22的产生增加；研究还在银屑病病变皮肤中检测到AOAH蛋白以及共表达AOAH和CD1a的细胞，而在健康皮肤中则未检测到相关表达，提示AOAH可能参与了银屑病病理过程。
5.3 盆腔疼痛
近年来YANG等课题组［27-29］的研究报道了AOAH与盆腔疼痛之间的密切关系。研究［27］使用伪狂犬病毒诱导的小鼠神经源性膀胱炎模型来诱导异常性盆腔疼痛，发现正常情况下不能在野生型小鼠骶髓中检测到AOAH的表达，而在伪狂犬病毒感染后可以检测到相关表达；在诱发痛觉刺激后，Aoah基因缺陷小鼠表现出更明显的盆腔疼痛超敏反应。此外，研究者在膀胱-脑轴多个部位的神经元中检测到AOAH的表达，且观察到Aoah基因缺陷小鼠膀胱中肥大细胞聚积增多，尿路上皮病变增加，膀胱血管内皮生长因子（vascular endothelial growth factor，VEGF）水平显著升高，进一步明确了AOAH在调节盆腔疼痛严重程度中的潜在机制及重要作用。通过脂质组学分析发现，Aoah基因缺陷小鼠骶髓中花生四烯酸（arachidonic acid，AA）及其代谢产物前列腺素E2（prostaglandin E2，PGE2）水平显著升高，而AA的代谢产物与炎症、疼痛密切相关［28，30］。研究［28］发现，AOAH表现出不依赖辅酶A的转移酶活性，介导AA整合于磷脂酰乙醇胺中，缺乏AOAH将导致结合膜AA减少及游离AA增多，进而导致AA代谢产物（如PGE2）增多，致使PGE2受体1亚型（prostaglandin E receptor 1，EP1）活化增多，增强感觉输入，从而加重盆腔疼痛。
AOAH脱酰灭活LPS还会产生其他影响。有研究［7］发现，AOAH对肠道微生物群衍生的内源性LPS的灭活会影响DC对辅助性T细胞17（helper T cell 17，Th17）的极化。Th17对于黏膜防御非常重要，其失调可引起免疫炎症失衡，导致自身免疫性疾病等不良后果［37-39］。JANELSINS等［7］发现，表达LPS的革兰阴性菌群可促进抗原特异性Th17细胞的分化，同时鉴定出1个兼具高表达AOAH和极化Th17能力的CD103+ CD116+ ALDH-（乙醛脱氢酶，aldehyde dehydrogenase）DC亚群；体外研究显示，Aoah基因缺陷小鼠结肠DC产生的IL-6和诱导极化的Th17减少，调节性T细胞（regulatory T cell，Treg）增多。AOAH脱酰灭活LPS影响肠道内微生物信号从而调节Th17反应，因此可以进一步探索Th17相关自身免疫性疾病中AOAH可能发挥的作用及机制。此外，LU等［40］研究发现，AOAH脱酰灭活LPS还可影响B细胞的增殖和多克隆抗体的生成。
The manuscript was drafted and revised by WU Zhenkai, DENG Bo and PAN Yu. The writing of the manuscript was guided by DING Feng. All the authors have read the last version of paper and consented for submission.
利益冲突声明
所有作者声明不存在利益冲突。
All authors disclose no relevant conflict of interests.
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... AOAH不仅能灭活LPS从而减轻感染所引起的炎症损伤，还能促进机体脱离LPS诱导的免疫耐受状态，恢复正常免疫应答与抵御再次感染的能力［1］.LU等［1］在给小鼠腹腔注射小剂量LPS或磷酸盐缓冲液（phosphate buffer saline，PBS）后，在不同时间测量血浆白介素-6（interleukin-6，IL-6）、正常T细胞表达和分泌的活性调节蛋白（regulated upon activation normal T expressed and secreted，RANTES）等因子水平以评估小鼠再次应对LPS的免疫应答能力；结果显示野生型小鼠与Aoah基因缺陷小鼠应对第1次LPS刺激产生的免疫应答能力没有差异，但是Aoah基因缺陷小鼠对第2次LPS刺激产生免疫应答的时间明显延长，缺乏AOAH所致的免疫耐受延长进一步损害小鼠控制感染的能力，而过表达Aoah可以避免以上免疫耐受的延长.进一步研究发现，缺乏AOAH所致的LPS持续存在会延长巨噬细胞重编程的时间［20-21］，在此期间表现为免疫耐受，机体应对感染反应迟缓，炎症消退减慢，死亡率升高［21］.因此，AOAH对于机体恢复免疫稳态，产生正常免疫应答能力抵御感染至关重要. ...
... ［1］在给小鼠腹腔注射小剂量LPS或磷酸盐缓冲液（phosphate buffer saline，PBS）后，在不同时间测量血浆白介素-6（interleukin-6，IL-6）、正常T细胞表达和分泌的活性调节蛋白（regulated upon activation normal T expressed and secreted，RANTES）等因子水平以评估小鼠再次应对LPS的免疫应答能力；结果显示野生型小鼠与Aoah基因缺陷小鼠应对第1次LPS刺激产生的免疫应答能力没有差异，但是Aoah基因缺陷小鼠对第2次LPS刺激产生免疫应答的时间明显延长，缺乏AOAH所致的免疫耐受延长进一步损害小鼠控制感染的能力，而过表达Aoah可以避免以上免疫耐受的延长.进一步研究发现，缺乏AOAH所致的LPS持续存在会延长巨噬细胞重编程的时间［20-21］，在此期间表现为免疫耐受，机体应对感染反应迟缓，炎症消退减慢，死亡率升高［21］.因此，AOAH对于机体恢复免疫稳态，产生正常免疫应答能力抵御感染至关重要. ...
... AOAH在肝脏感染性疾病中同样扮演重要角色［6，19］.肝、脾是清除血液中LPS的主要器官.SHAO等［6］发现，在静脉注射LPS后，相较于野生型小鼠，Aoah基因缺陷小鼠肝脏中炎症细胞浸润更加显著，肝、脾肿大也更加明显，而外源性重组AOAH可以恢复Aoah基因缺陷小鼠脱酰化LPS的能力，并且逆转由LPS引起的肝、脾肿大.此外，LIU等［19］研究发现，热休克蛋白A12A（heat shock protein family A member 12A，Hspa12a）基因敲除小鼠在LPS诱导后表现出更严重的急性肝损伤，AOAH的表达也明显减少，而过表达Aoah可以逆转在LPS诱导后由于HSPA12A缺乏所引起的肝细胞焦亡；进一步研究显示，HSPA12A通过与过氧化物酶体增殖物激活受体γ辅激活因子1α（peroxisome proliferator-activated receptor-γ coactivator-1α，PGC-1α）相互作用上调AOAH表达从而灭活LPS，进而抑制含半胱氨酸的天冬氨酸蛋白水解酶-11（caspase-11）介导的肝细胞焦亡.深入对AOAH功能与通路的研究有助于我们更好地了解肝脏感染性疾病的病理生理过程，并寻找新的治疗靶点. ...
... ［6］发现，在静脉注射LPS后，相较于野生型小鼠，Aoah基因缺陷小鼠肝脏中炎症细胞浸润更加显著，肝、脾肿大也更加明显，而外源性重组AOAH可以恢复Aoah基因缺陷小鼠脱酰化LPS的能力，并且逆转由LPS引起的肝、脾肿大.此外，LIU等［19］研究发现，热休克蛋白A12A（heat shock protein family A member 12A，Hspa12a）基因敲除小鼠在LPS诱导后表现出更严重的急性肝损伤，AOAH的表达也明显减少，而过表达Aoah可以逆转在LPS诱导后由于HSPA12A缺乏所引起的肝细胞焦亡；进一步研究显示，HSPA12A通过与过氧化物酶体增殖物激活受体γ辅激活因子1α（peroxisome proliferator-activated receptor-γ coactivator-1α，PGC-1α）相互作用上调AOAH表达从而灭活LPS，进而抑制含半胱氨酸的天冬氨酸蛋白水解酶-11（caspase-11）介导的肝细胞焦亡.深入对AOAH功能与通路的研究有助于我们更好地了解肝脏感染性疾病的病理生理过程，并寻找新的治疗靶点. ...
... AOAH在肝脏感染性疾病中同样扮演重要角色［6，19］.肝、脾是清除血液中LPS的主要器官.SHAO等［6］发现，在静脉注射LPS后，相较于野生型小鼠，Aoah基因缺陷小鼠肝脏中炎症细胞浸润更加显著，肝、脾肿大也更加明显，而外源性重组AOAH可以恢复Aoah基因缺陷小鼠脱酰化LPS的能力，并且逆转由LPS引起的肝、脾肿大.此外，LIU等［19］研究发现，热休克蛋白A12A（heat shock protein family A member 12A，Hspa12a）基因敲除小鼠在LPS诱导后表现出更严重的急性肝损伤，AOAH的表达也明显减少，而过表达Aoah可以逆转在LPS诱导后由于HSPA12A缺乏所引起的肝细胞焦亡；进一步研究显示，HSPA12A通过与过氧化物酶体增殖物激活受体γ辅激活因子1α（peroxisome proliferator-activated receptor-γ coactivator-1α，PGC-1α）相互作用上调AOAH表达从而灭活LPS，进而抑制含半胱氨酸的天冬氨酸蛋白水解酶-11（caspase-11）介导的肝细胞焦亡.深入对AOAH功能与通路的研究有助于我们更好地了解肝脏感染性疾病的病理生理过程，并寻找新的治疗靶点. ...
... ［19］研究发现，热休克蛋白A12A（heat shock protein family A member 12A，Hspa12a）基因敲除小鼠在LPS诱导后表现出更严重的急性肝损伤，AOAH的表达也明显减少，而过表达Aoah可以逆转在LPS诱导后由于HSPA12A缺乏所引起的肝细胞焦亡；进一步研究显示，HSPA12A通过与过氧化物酶体增殖物激活受体γ辅激活因子1α（peroxisome proliferator-activated receptor-γ coactivator-1α，PGC-1α）相互作用上调AOAH表达从而灭活LPS，进而抑制含半胱氨酸的天冬氨酸蛋白水解酶-11（caspase-11）介导的肝细胞焦亡.深入对AOAH功能与通路的研究有助于我们更好地了解肝脏感染性疾病的病理生理过程，并寻找新的治疗靶点. ...
1
... AOAH不仅能灭活LPS从而减轻感染所引起的炎症损伤，还能促进机体脱离LPS诱导的免疫耐受状态，恢复正常免疫应答与抵御再次感染的能力［1］.LU等［1］在给小鼠腹腔注射小剂量LPS或磷酸盐缓冲液（phosphate buffer saline，PBS）后，在不同时间测量血浆白介素-6（interleukin-6，IL-6）、正常T细胞表达和分泌的活性调节蛋白（regulated upon activation normal T expressed and secreted，RANTES）等因子水平以评估小鼠再次应对LPS的免疫应答能力；结果显示野生型小鼠与Aoah基因缺陷小鼠应对第1次LPS刺激产生的免疫应答能力没有差异，但是Aoah基因缺陷小鼠对第2次LPS刺激产生免疫应答的时间明显延长，缺乏AOAH所致的免疫耐受延长进一步损害小鼠控制感染的能力，而过表达Aoah可以避免以上免疫耐受的延长.进一步研究发现，缺乏AOAH所致的LPS持续存在会延长巨噬细胞重编程的时间［20-21］，在此期间表现为免疫耐受，机体应对感染反应迟缓，炎症消退减慢，死亡率升高［21］.因此，AOAH对于机体恢复免疫稳态，产生正常免疫应答能力抵御感染至关重要. ...
2
... AOAH不仅能灭活LPS从而减轻感染所引起的炎症损伤，还能促进机体脱离LPS诱导的免疫耐受状态，恢复正常免疫应答与抵御再次感染的能力［1］.LU等［1］在给小鼠腹腔注射小剂量LPS或磷酸盐缓冲液（phosphate buffer saline，PBS）后，在不同时间测量血浆白介素-6（interleukin-6，IL-6）、正常T细胞表达和分泌的活性调节蛋白（regulated upon activation normal T expressed and secreted，RANTES）等因子水平以评估小鼠再次应对LPS的免疫应答能力；结果显示野生型小鼠与Aoah基因缺陷小鼠应对第1次LPS刺激产生的免疫应答能力没有差异，但是Aoah基因缺陷小鼠对第2次LPS刺激产生免疫应答的时间明显延长，缺乏AOAH所致的免疫耐受延长进一步损害小鼠控制感染的能力，而过表达Aoah可以避免以上免疫耐受的延长.进一步研究发现，缺乏AOAH所致的LPS持续存在会延长巨噬细胞重编程的时间［20-21］，在此期间表现为免疫耐受，机体应对感染反应迟缓，炎症消退减慢，死亡率升高［21］.因此，AOAH对于机体恢复免疫稳态，产生正常免疫应答能力抵御感染至关重要. ...
