Sex and SP-A2 Dependent NAD(H) Redox Alterations in Mouse Alveolar Macrophages in Response to Ozone Exposure: Potential Implications for COVID-19.

He N Xu,Zhenwu Lin,Shaili Amatya,Chintan K Gandhi,Lin Z Li,Joanna Floros,Yunhua Wang

doi:10.3390/antiox9100915

He N Xu, Zhenwu Lin + Show 5 more

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https://doi.org/10.3390/antiox9100915

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Abstract

Co-enzyme nicotinamide adenine dinucleotide (NAD(H)) redox plays a key role in macrophage function. Surfactant protein (SP-) A modulates the functions of alveolar macrophages (AM) and ozone (O3) exposure in the presence or absence of SP-A and reduces mouse survival in a sex-dependent manner. It is unclear whether and how NAD(H) redox status plays a role in the innate immune response in a sex-dependent manner. We investigated the NAD(H) redox status of AM from SP-A2 and SP-A knockout (KO) mice in response to O3 or filtered air (control) exposure using optical redox imaging technique. We found: (i) In SP-A2 mice, the redox alteration of AM in response to O3 showed sex-dependence with AM from males being significantly more oxidized and having a higher level of mitochondrial reactive oxygen species than females; (ii) AM from KO mice were more oxidized after O3 exposure and showed no sex differences; (iii) AM from female KO mice were more oxidized than female SP-A2 mice; and (iv) Two distinct subpopulations characterized by size and redox status were observed in a mouse AM sample. In conclusions, the NAD(H) redox balance in AM responds to O3 in a sex-dependent manner and the innate immune molecule, SP-A2, contributes to this observed sex-specific redox response.

Highlights

In the lung, more than 80% of cells in the bronchoalveolar lavage (BAL) are macrophages [1,2].Macrophages engulf and digest cellular debris, cancer cells, foreign substances, and bacteria by phagocytosis
We found that ozone exposure altered the NAD(H) redox status of mouse alveolar macrophages (AM) in a sex-dependent manner in the presence of Surfactant protein (SP-)A2, and SP-A2 may play a role in females in counteracting O3 -induced oxidation by modulating the NAD(H) redox status
Our results indicate that an ozone exposure of 2 ppm for 3 h resulted in a significantly lower NADH level and higher optical redox ratio in AM from male SP-A2 mice

Summary

Introduction

More than 80% of cells in the bronchoalveolar lavage (BAL) are macrophages [1,2].Macrophages engulf and digest cellular debris, cancer cells, foreign substances, and bacteria by phagocytosis. More than 80% of cells in the bronchoalveolar lavage (BAL) are macrophages [1,2]. Macrophages play a critical role in nonspecific defense (innate immunity) and are important as antigen presenters to T cells [3]. Macrophages play important pro-inflammatory and anti-inflammatory roles depending on the specific conditions and modulate immune reactions through cytokine release [4]. Metabolism has profound influence on macrophage polarization/activation and pathogenesis [5]. Macrophage activation is critically supported by metabolic shifts. Pro-inflammatory macrophages have an anaerobic metabolic profile based on glycolysis whereas anti-inflammatory macrophages generally rely on oxidative phosphorylation (OXPHOS) for energy generation [6,7]. A change in the NAD+ /NADH ratio (redox shift) can profoundly affect metabolism, including reactions of glycolysis and the tricarboxylic acid cycle (TCA)

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