Succinate Dehydrogenase Regulates Homeostasis and Metabolic Integrity of Alveolar Macrophages

Lung tissue-resident macrophages (TRMs), including alveolar macrophages (AMs) and interstitial macrophages (IMs), are pivotal in maintaining both immune defense and tissue homeostasis. Although the distinct functional roles of these macrophage populations are well recognized, the specific metabolic pathways that support their functions are not fully understood. Comparative RNA sequencing analysis identified Sdha, a key enzyme in mitochondrial metabolism, as one of the most highly expressed and differentially regulated genes involved in metabolic pathways in AMs relative to IMs. This finding led us to investigate the role of succinate dehydrogenase complex subunit A (SDHA) in regulating AM metabolism and function. Here, we demonstrated that SDHA is crucial for maintaining AM homeostasis. Deletion of SDHA resulted in a significant reduction in AM populations without affecting IMs, highlighting an AM-specific requirement for SDHA. In the absence of SDHA, AMs underwent metabolic reprogramming towards glycolysis compared with IMs, along with significant transcriptional changes and cell death. Furthermore, SDHA-deficient AMs showed lipid accumulation and increased endoplasmic reticulum (ER) stress. These findings establish SDHA as a crucial regulator of AM metabolism and underscore the importance of maintaining metabolic integrity for AM function and survival within the lung microenvironment. Overall design: RNA-seq profiling of FACS-sorted CD45+ CD11c+ F4/80+ SiglecF+ CD11b- alveolar macrophages from wildtype and Sdha-flox LysM-Cre knockout mice