Genetic Blockade of NAAA Cell-specifically Regulates Fatty Acid Ethanolamides (FAEs) Metabolism and Inflammatory Responses

Xiaohua Xie; Yitian Li; Sennan Xu; Pan Zhou; Longhe Yang; Yaping Xu; Yan Qiu; Yungang Yang; Yuhang Li

doi:10.3389/fphar.2021.817603

Genetic Blockade of NAAA Cell-specifically Regulates Fatty Acid Ethanolamides (FAEs) Metabolism and Inflammatory Responses

Front Pharmacol. 2022 Jan 7:12:817603. doi: 10.3389/fphar.2021.817603. eCollection 2021.

Authors

Xiaohua Xie^{1

2}, Yitian Li^{3

4}, Sennan Xu³, Pan Zhou^{3

5}, Longhe Yang⁶, Yaping Xu⁷, Yan Qiu^{3

4}, Yungang Yang^{1

2}, Yuhang Li^{8

9}

Affiliations

¹ Department of Pediatrics, The First Affiliated Hospital of Xiamen University, Xiamen, China.
² School of Medicine, Institute of Pediatrics, Xiamen University, Xiamen, China.
³ Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, School of Medicine, Eye Institute of Xiamen University, Xiamen University, Xiamen, China.
⁴ Department of Clinical Pharmacy, The Third Hospital of Mianyang/Sichuan Mental Health Center, Mianyang, China.
⁵ Department of Pathology, Qilu Hospital, Shandong University, Jinan, China.
⁶ Technical Innovation Center for Utilization of Marine Biological Resources, Third Institute of Oceanography, Ministry of Natural Resources, Xiamen, China.
⁷ Key Laboratory of Functional and Clinical Translational Medicine, Xiamen Medical College, Fujian Province University, Xiamen, China.
⁸ CAS Key Laboratory of Design and Assembly of Functional Nanostructures and Fujian Provincial Key Laboratory of Nanomaterials, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fujian, China.
⁹ Xiamen Institute of Rare-earth Materials, Haixi Institutes, Chinese Academy of Sciences, Fujian, China.

Abstract

N-Acylethanolamine acid amidase (NAAA) is a lysosomal enzyme responsible for the hydrolysis of fatty acid ethanolamides (FAEs). However, the role of NAAA in FAEs metabolism and regulation of pain and inflammation remains mostly unknown. Here, we generated NAAA-deficient (NAAA^-/-) mice using CRISPR-Cas9 technique, and found that deletion of NAAA increased PEA and AEA levels in bone marrow (BM) and macrophages, and elevated AEA levels in lungs. Unexpectedly, genetic blockade of NAAA caused moderately effective anti-inflammatory effects in lipopolysaccharides (LPS)-induced acute lung injury (ALI), and poor analgesic effects in carrageenan-induced hyperalgesia and sciatic nerve injury (SNI)-induced mechanical allodynia. These data contrasted with acute (single dose) or chronic NAAA inhibition by F96, which produced marked anti-inflammation and analgesia in these models. BM chimera experiments indicated that these phenotypes were associated with the absence of NAAA in non-BM cells, whereas deletion of NAAA in BM or BM-derived cells in rodent models resulted in potent analgesic and anti-inflammatory phenotypes. When combined, current study suggested that genetic blockade of NAAA regulated FAEs metabolism and inflammatory responses in a cell-specifical manner.

Keywords: N-acylethanolamine acid amidase (NAAA); analgesic tolerance; anandamide (AEA); fatty acid ethanolamides (FAEs); palmitoylethanolamide (PEA).