Aoah, encoding acyloxyacyl hydrolase, is an important enzyme. It degrades and inactivates lipopolysaccharide (LPS), a cell wall component of Gram-negative bacteria, thus playing a crucial role in innate immune response and inflammation regulation. AOAH-related pathways involve Toll-like receptor 4 (TLR4) signaling and Caspase-11-mediated pyroptosis. Genetic models, especially KO mouse models, have been instrumental in studying its functions [1,5,7].

In KO mouse models, AOAH deficiency leads to various issues. In sepsis, it promotes LPS-induced acute liver injury as HSPA12A-mediated AOAH expression is suppressed, enhancing Caspase-11-mediated hepatocyte pyroptosis [1]. In interstitial cystitis pain models, AOAH-deficient mice have elevated pelvic pain, altered AA-containing phospholipid pools, and microglial-mediated pain modulation [2,6]. Also, they exhibit voiding dysfunction, with enlarged bladders and increased non-voiding contractions [3]. In kidney injury, AOAH deletion exacerbates injury and fibrosis [4]. In the lung, AOAH-deficient mice have more tolerant alveolar macrophages, reduced antibacterial defenses, and greater susceptibility to Pseudomonas aeruginosa infection [5]. In stroke models, AOAH deficiency increases neutrophil extravasation, BBB disruption, and worsens stroke outcomes [7]. In bone metabolism, adult Aoah -/- mice show chronic inflammation and osteopenic phenotype due to enhanced osteoclast differentiation [8].

In conclusion, Aoah is essential for maintaining normal physiological functions by inactivating LPS and regulating inflammation. AOAH KO mouse models have revealed its significant roles in multiple disease areas such as sepsis, interstitial cystitis, kidney injury, pulmonary infections, stroke, and bone loss-related disorders, providing valuable insights into disease mechanisms and potential therapeutic targets.

References:

1. Liu, Jiali, Du, Shuya, Kong, Qiuyue, Ding, Zhengnian, Liu, Li. 2020. HSPA12A attenuates lipopolysaccharide-induced liver injury through inhibiting caspase-11-mediated hepatocyte pyroptosis via PGC-1α-dependent acyloxyacyl hydrolase expression. In Cell death and differentiation, 27, 2651-2667. doi:10.1038/s41418-020-0536-x. https://pubmed.ncbi.nlm.nih.gov/32332915/

2. Yang, Wenbin, Yaggie, Ryan E, Schaeffer, Anthony J, Klumpp, David J. 2020. AOAH remodels arachidonic acid-containing phospholipid pools in a model of interstitial cystitis pain: A MAPP Network study. In PloS one, 15, e0235384. doi:10.1371/journal.pone.0235384. https://pubmed.ncbi.nlm.nih.gov/32925915/

3. Aguiniga, Lizath M, Searl, Timothy J, Rahman-Enyart, Afrida, Schaeffer, Anthony J, Klumpp, David J. 2020. Acyloxyacyl hydrolase regulates voiding activity. In American journal of physiology. Renal physiology, 318, F1006-F1016. doi:10.1152/ajprenal.00442.2019. https://pubmed.ncbi.nlm.nih.gov/32003596/

4. Wu, Zhenkai, Deng, Bo, Shen, Yuqi, Pan, Yu, Ding, Feng. 2024. Acyloxyacyl Hydrolase Protects against Kidney Injury via Inhibition of Tubular CD74-Macrophage Crosstalk. In International journal of biological sciences, 20, 3061-3075. doi:10.7150/ijbs.91237. https://pubmed.ncbi.nlm.nih.gov/38904010/

5. Cheng, Xiaofang, Jiang, Wei, Chen, Yeying, Tang, Jianguo, Lu, Mingfang. 2023. Acyloxyacyl hydrolase promotes pulmonary defense by preventing alveolar macrophage tolerance. In PLoS pathogens, 19, e1011556. doi:10.1371/journal.ppat.1011556. https://pubmed.ncbi.nlm.nih.gov/37498977/

6. Rahman-Enyart, Afrida, Yaggie, Ryan E, Bollinger, Justin L, Schaeffer, Anthony J, Klumpp, David J. 2022. Acyloxyacyl hydrolase regulates microglia-mediated pelvic pain. In PloS one, 17, e0269140. doi:10.1371/journal.pone.0269140. https://pubmed.ncbi.nlm.nih.gov/35980963/

7. Zhu, Yuanbo, Hu, Yue, Liu, Zhongwang, Zhao, Bing-Qiao, Fan, Wenying. 2024. The LPS-inactivating enzyme acyloxyacyl hydrolase protects the brain from experimental stroke. In Translational research : the journal of laboratory and clinical medicine, 270, 42-51. doi:10.1016/j.trsl.2024.03.007. https://pubmed.ncbi.nlm.nih.gov/38522823/

8. Cheng, Xu, Song, Xiaoting, Li, Zhiyan, Zhang, Liwei, Hong, Dun. 2022. Acyloxyacyl hydrolase deficiency induces chronic inflammation and bone loss in male mice. In Journal of molecular medicine (Berlin, Germany), 100, 1599-1616. doi:10.1007/s00109-022-02252-w. https://pubmed.ncbi.nlm.nih.gov/36112153/