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

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

doi:10.3389/fphar.2021.817603

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.

Highlights

Fatty acid ethanolamides (FAEs) are endogenous lipids that participate in the modulation of many physiological functions (Piomelli and Sasso, 2014)
Western blot showed that 29 kDa (β-subunit) bands were hardly detectable in brain, lungs, skin and spleen samples from N-acylethanolamine acid amidase (NAAA)-/- mice (Figure 1B)
We showed that genetic blockade of NAAA regulates fatty acid ethanolamides (FAEs) metabolism and caused analgesic and anti-inflammatory tolerance in a tissue-specifical manner

Summary

Introduction

Fatty acid ethanolamides (FAEs) are endogenous lipids that participate in the modulation of many physiological functions (Piomelli and Sasso, 2014). AEA, OEA and PEA are mainly metabolized by fatty acid amide hydrolase (FAAH) and N-acylethanolamine acid amidase (NAAA) (McKinney and Cravatt, 2005; Tsuboi et al, 2007a). The roles of FAAH on metabolism of FAEs have been well studied (Roques et al, 2012; Piomelli and Sasso, 2014; Carnevali et al, 2017) Both FAAH-deficient mice and pharmacological administration of FAAH inhibitors in animal result in significant increment of AEA (7∼15-fold), OEA (13-fold) and PEA (4∼8-fold) in various organs, e.g., brain and liver (Ahn et al, 2011; Li et al, 2012a). Contrary to FAAH, the role of NAAA in FAEs metabolism remains mostly unclear

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Conclusion