Impaired macrophage autophagy increases the immune response in obese mice by promoting proinflammatory macrophage polarization

Abstract

Recent evidence that excessive lipid accumulation can decrease cellular levels of autophagy and that autophagy regulates immune responsiveness suggested that impaired macrophage autophagy may promote the increased innate immune activation that underlies obesity. Primary bone marrow-derived macrophages (BMDM) and peritoneal macrophages from high-fat diet (HFD)-fed mice had decreased levels of autophagic flux indicating a generalized impairment of macrophage autophagy in obese mice. To assess the effects of decreased macrophage autophagy on inflammation, mice with a Lyz2-Cre-mediated knockout of Atg5 in macrophages were fed a HFD and treated with low-dose lipopolysaccharide (LPS). Knockout mice developed systemic and hepatic inflammation with HFD feeding and LPS. This effect was liver specific as knockout mice did not have increased adipose tissue inflammation. The mechanism by which the loss of autophagy promoted inflammation was through the regulation of macrophage polarization. BMDM and Kupffer cells from knockout mice exhibited abnormalities in polarization with both increased proinflammatory M1 and decreased anti-inflammatory M2 polarization as determined by measures of genes and proteins. The heightened hepatic inflammatory response in HFD-fed, LPS-treated knockout mice led to liver injury without affecting steatosis. These findings demonstrate that autophagy has a critical regulatory function in macrophage polarization that downregulates inflammation. Defects in macrophage autophagy may underlie inflammatory disease states such as the decrease in macrophage autophagy with obesity that leads to hepatic inflammation and the progression to liver injury.

Antagonizing peroxisome proliferator‐activated receptor γ facilitates M1‐to‐M2 shift of microglia by enhancing autophagy via the LKB1–AMPK signaling pathway

“…Numerous studies have shown the important roles of autophagy in microglial inflammation and phenotype shift (Liu et al., 2015; Yang et al., 2014; Zhang, Guo, Zhao, Shao & Zheng, 2016). However, whether PPARγ alters LPS‐induced microglial polarization by modulating autophagy remains unclear.…”

Autophagy deficiency in myeloid cells increases susceptibility to obesity-induced diabetes and experimental colitis

“…The glucose profile of Atg5 cKO mice fed high-fat diet is not higher than that of Atg5 cWT mice fed high-fat diet. 47 The dissimilar glucose profile between Atg5 cKO mice fed high-fat diet and Atg7 cKO-ob/ ob mice appears to be due to the difference between high-fat diet and obesity due to Lep knockout in ob/ob mice. Obesity due to LEP deficiency can impose more severe metabolic stress compared to high-fat diet.…”

“…A recent paper reports that myeloid cell-specific Atg5 deletion leads to increased tissue inflammation and injury specifically in the liver after high-fat diet feeding in combination with LPS administration. 47 However, the role of myeloid cell autophagy in metainflammation of tissues other than liver or in the development of T2D has not been demonstrated. The glucose profile of Atg5 cKO mice fed high-fat diet is not higher than that of Atg5 cWT mice fed high-fat diet.…”

Innate immunity in diabetes and diabetic nephropathy

“…Systemic impairment of autophagy by haploinsufficiency of the essential autophagy gene (Atg7 +/-) in ob/ob mice aggravated insulin resistance with increased lipid contents and inflammatory changes 120 . Furthermore, mice with a Lyz2-Cre-mediated knockout of Atg5 in macrophages fed a HFD and administered LPS demonstrated systemic and hepatic inflammation 121 . Defects in macrophage autophagy results in abnormal polarization, with increased M1 and decreased M2 macrophage subtypes, and enhanced hepatic inflammation and liver injury in obesity 121 .…”

“…Furthermore, mice with a Lyz2-Cre-mediated knockout of Atg5 in macrophages fed a HFD and administered LPS demonstrated systemic and hepatic inflammation 121 . Defects in macrophage autophagy results in abnormal polarization, with increased M1 and decreased M2 macrophage subtypes, and enhanced hepatic inflammation and liver injury in obesity 121 .…”