Sirtuin 2 Dysregulates Autophagy in High-Fat-Exposed Immune-Tolerant Macrophages

Abstract

Obesity increases morbidity and resource utilization in sepsis patients. The immune response in sepsis transitions from an endotoxin-responsive hyper- to an endotoxin-tolerant hypo-inflammatory phase. The majority of sepsis mortality occurs during hypo-inflammation. We reported prolonged hypo-inflammation with increased sirtuin 2 (SIRT2) expression in obese-septic mice. The effect of direct exposure to high-fat/free fatty acid (FFA) and the role of SIRT2 in immune cells during the transition to hypo-inflammation is not well-understood. Autophagy, a degradation process of damaged protein/organelles, is dysregulated during sepsis. Here, we investigated the effect of direct FFA exposure and the role of SIRT2 expression on autophagy as macrophages transition from hyper-to hypo-inflammation. We found, FFA-exposed RAW 264.7 cells with lipopolysaccharide (LPS) stimulation undergo endotoxin-sensitive (“sensitive”) hyper- followed by endotoxin tolerant (“tolerant”) hypo-inflammatory phases; SIRT2 expression increases significantly in tolerant cells. Autophagy proteins LC3b-II, and beclin-1 increase in FFA-sensitive and decrease in tolerant cells; p62 expressions continue to accumulate in tolerant cells. We observed that SIRT2 directly deacetylates α-tubulin and impairs autophagy clearance. Importantly, we find SIRT2 inhibitor AK-7 treatment during endotoxin tolerant phase reverses autophagy dysregulation with improved autophagy clearance in FFA-tolerant cells. Thus, we report impaired autophagosome formation and autophagy clearance via increased SIRT2 expression in FFA-exposed tolerant macrophages.

Transcriptome Analysis of Retinoic Acid-Inducible Gene I Overexpression Reveals the Potential Genes for Autophagy-Related Negative Regulation

“…OTUD7B serves as a deubiquitinase of P62/SQSTM1 and enhances the degradation of IRF-3 [51,52]. SIRT2 dysregulates autophagy in highfat-exposed immune-tolerant macrophages, and the knockdown of SIRT2 increases basal autophagy [53][54][55]. With the combined analysis of DEGs and reports mentioned above, our study indicated that PTPN22, PRKN, OTUD7B, and SIRT2 genes were strongly correlated to the negative regulation of excessive expression of RIG-I.…”

SIRT2-PFKP interaction dysregulates phagocytosis in macrophages with acute ethanol-exposure

“…The biological-context-driven regulation of LC3 and autophagy need further evaluation. Also, while we have implicated SIRT2 in dysregulated autophagy with high-fat exposure, the effect of ethanol-exposure and SIRT2-PFKP interaction on autophagy in ethanol-exposed macrophages needs further evaluation ( 77 ).…”

Necroptosis-associated long noncoding RNAs can predict prognosis and differentiate between cold and hot tumors in ovarian cancer

“…SIRT2 is an NAD+-dependent deacetylase and is the only sirtuin protein found in the cytoplasm, mitochondria, and nucleus [36]. It can regulate autophagy in high-fat-exposed immune cells ( 39 ). Another member of the spermatogenesis-related protein family, SPATA2, is associated with the autoimmune disorder of psoriasis ( 40 ).…”