Sirtuin-dependent metabolic and epigenetic regulation of macrophages during tuberculosis

**Background:** Macrophages are key phagocytic cells that respond to Mycobacterium tuberculosis (MTB) infection using antimicrobial mechanisms including autophagy, reactive oxygen species (ROS), and reactive nitrogen species (RNS). MTB employs evasion strategies, including epigenetic modifications such as DNA hypermethylation and histone acetylation, to survive within macrophages. Macrophages polarize into pro-inflammatory M1 (bactericidal) or anti-inflammatory M2 (permissive) phenotypes, with distinct metabolic profiles. Sirtuins (SIRT1-7) are NAD+-dependent histone/protein deacetylases that link cellular metabolism to epigenetic regulation. This review summarizes recent research on how glucose metabolism and sirtuin activity regulate macrophage activation, polarization, and autophagy during TB.

**Methods:** This is a narrative review synthesizing published literature on glucose metabolism, sirtuin biology, and epigenetic regulation in macrophages during TB infection. The authors integrate findings from their own proteomics, transcriptomics (RNA-seq), and metabolomics studies of human monocyte-derived M1 and M2 macrophages infected with MTB, alongside data from mouse models and other published studies.

**Key Results:** Glycolysis is upregulated in M1 macrophages, producing ATP, acetyl-CoA (ac-CoA), and NAD+. Ac-CoA is a co-substrate for histone acetyltransferases, while NAD+ is essential for sirtuin deacetylase activity. M1 macrophages exhibit increased glycolysis, reduced TCA cycle activity, and elevated ROS/RNS production via NOX2 and iNOS/NOS2, enabling bactericidal function. M2 macrophages rely more on oxidative phosphorylation. MTB infection induces a biphasic metabolic switch: early M1-like glycolysis (up to 8 hr) transitioning to M2-like oxidative metabolism (24-48 hr). Sirtuins are differentially expressed in human M1 vs. M2 macrophages: SIRT2 is higher in M2 macrophages, and its pharmacological inhibition (e.g., AGK2) increases autophagy and MTB killing. SIRT1 activation (e.g., resveratrol) induces autophagy and reduces inflammation via RelA/p65 deacetylation. SIRT3 downregulation in MTB-infected macrophages leads to mitochondrial ROS accumulation and cell death; SIRT3 activation (honokiol) reduces bacterial burden. SIRT5 is upregulated in M1 macrophages and regulates arginine metabolism, NO production, and one-carbon metabolism via desuccinylation of CPS1 and SHMT2. SIRT6 facilitates MTB survival by modulating cholesterol accumulation. NAD+ levels are critical: MTB infection depletes NAD+, and NAD+ replenishment protects macrophages from cell death. The NAD+ salvage pathway and de novo synthesis from tryptophan (via QPRT) are both important for macrophage function. Serine biosynthesis from glycolysis feeds one-carbon metabolism to produce SAM for histone/DNA methylation; NO in M1 macrophages poisons vitamin B12, disrupting this pathway and reducing methylation.

**Clinical Implications:** Sirtuin modulators represent promising immunotherapeutic targets for TB. SIRT1 activators (resveratrol, metformin) and SIRT2 inhibitors (AGK2) enhance anti-TB drug efficacy in preclinical models. SIRT3 activators (honokiol) may protect macrophages from MTB-induced damage. Targeting NAD+ biosynthesis—specifically MTB-specific QPRT or nadA/nadB enzymes—could selectively impair bacterial survival while preserving host macrophage function. The authors emphasize that human and mouse macrophages differ in sirtuin-dependent regulation, highlighting the need for human-focused studies. Future work should use stable isotope tracing (glucose, glutamine, arginine) to dynamically map metabolic-epigenetic crosstalk in polarized macrophages over the course of infection.