The metabolic ER stress sensor IRE1α suppresses alternative activation of macrophages and impairs energy expenditure in obesity

Abstract

Obesity is associated with metabolic inflammation and endoplasmic reticulum (ER) stress, both of which promote metabolic disease progression. Adipose tissue macrophages (ATMs) are key players orchestrating metabolic inflammation, and ER stress enhances macrophage activation. However, whether ER stress pathways underlie ATM regulation of energy homeostasis remains unclear. Here, we identified inositol-requiring enzyme 1α (IRE1α) as a critical switch governing M1-M2 macrophage polarization and energy balance. Myeloid-specific IRE1α abrogation in Ern1; Lyz2-Cre mice largely reversed high-fat diet (HFD)-induced M1-M2 imbalance in white adipose tissue (WAT) and blocked HFD-induced obesity, insulin resistance, hyperlipidemia and hepatic steatosis. Brown adipose tissue (BAT) activity, WAT browning and energy expenditure were significantly higher in Ern1; Lyz2-Cre mice. Furthermore, IRE1α ablation augmented M2 polarization of macrophages in a cell-autonomous manner. Thus, IRE1α senses protein unfolding and metabolic and immunological states, and consequently guides ATM polarization. The macrophage IRE1α pathway drives obesity and metabolic syndrome through impairing BAT activity and WAT browning.

Endoplasmic Reticulum Stress Sensor IRE1α Enhances IL-23 Expression by Human Dendritic Cells

“…P-S52-eIF2α was detected to a low extent in resting DCs and did not increase upon 2-DG treatment and PAMPs stimulation (Figure 7A), in agreement with a recent report showing that LPS did not affect eIF2α phosphorylation (44). The mRNA expression of DDIT3 /CHOP was enhanced by 2-DG and blunted by mannose in the presence of PAMPs (Figure 7B), thus suggesting that mannose may counter some of the mechanisms triggered by the stimuli by acting as a substrate for the formation of dolichol-linked oligosaccharide.…”

“…The interplay between the PERK and IRE1α routes through STAT3 (Figure 10) is supported by recent data showing that STAT3 plays a critical role in the activation of a non-canonical UPR cascade involving Ire1α and Xbp1 under combined cytokine stimulation (58). Our finding of a stable phosphorylation of eIF2α (Figure 7A) agrees with a recent report showing similar results in M2-polarized macrophages stimulated with LPS, thus suggesting that some stimuli activate the UPR in the absence of a stimulatory effect on eIF2α phosphorylation (44). …”

Myeloid-specific deletion of NOX2 prevents the metabolic and neurologic consequences of high fat diet

“…While cause and effect between macrophage reactivity and adipose pathology are not well established, data in this manuscript suggests that macrophage reactivity is a cause rather than a consequence of adiposopathy and mediates, at least in part, the pathologic processes of metabolic and neurologic dysfunction. This scenario is supported by other studies demonstrating that prevention of inflammatory signaling in myeloid cells not only prevents high-fat diet-induced obesity and metabolic dysfunction, but also increases brown adipose tissue activity, white adipose browning, and energy expenditure [64], [65]. While energy expenditure was not measured in the present study, the decreased expression of markers of ER stress in visceral adipose suggests improved adipose physiology.…”

Foundations of Immunometabolism and Implications for Metabolic Health and Disease

“…showed that classical macrophage markers of inflammation such as CD38 and CD274 are not induced in response to metabolic stimuli, which indicates that alternative activation pathways, including fatty acid-driven PPARγ signaling, may underlie metaflammatory phenotypes (Kratz et al, 2014). Interestingly, recent studies also support the concept that chronic ER stress in obesity may lead to inflammatory polarization in adipose tissue macrophages (Shan et al, 2017). It was also demonstrated that GPS2, a component of the co-repressor complex, restrains expression of pro-inflammatory mediators in ATMs.…”