Significance This study addresses a fundamentally important and widely debated issue in the field of inflammation, which is why inflammation can be simultaneously deleterious after injury and yet is essential for tissue repair. Recently, an important new paradigm has emerged in the macrophage field: Organs are replete with resident macrophages of embryonic origin, distinct from monocyte-derived macrophages. In this article, we use a new model of cardiac injury and show that distinct macrophage populations derived from embryonic and adult lineages are important determinants of tissue repair and inflammation, respectively. Our data suggest that therapeutics, which inhibit monocyte-derived macrophages and/or selectively harness the function of embryonic-derived macrophages, may serve as novel treatments for heart failure.

Background: Ceramide is a critical lipid mediator of cellular stress responses relating to inflammation and insulin resistance. Results: Palmitate and LPS synergistically induce macrophage de novo ceramide biosynthesis. Conclusion: TLR4 signaling via TRIF and MyD88 in combination with palmitate up-regulates ceramide synthesis through a non-transcriptional mechanism. Significance: Understanding how lipid excess intersects with inflammatory signaling may provide insights into the pathogenesis of metabolic disease.

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Obesity and diabetes are associated with excessive inflammation and impaired wound healing. Increasing evidence suggests that macrophage dysfunction is responsible for these inflammatory defects. In the setting of excess nutrients, particularly dietary saturated fatty acids (SFAs), activated macrophages develop lysosome dysfunction, which triggers activation of the NLRP3 inflammasome and cell death. The molecular pathways that connect lipid stress to lysosome pathology are not well understood, but may represent a viable target for therapy. Glutamine uptake is increased in activated macrophages leading us to hypothesize that in the context of excess lipids glutamine metabolism could overwhelm the mitochondria and promote the accumulation of toxic metabolites. To investigate this question we assessed macrophage lipotoxicity in the absence of glutamine using LPS-activated peritoneal macrophages exposed to the SFA palmitate. We found that glutamine deficiency reduced lipid induced lysosome dysfunction, inflammasome activation, and cell death. Under glutamine deficient conditions mTOR activation was decreased and autophagy was enhanced; however, autophagy was dispensable for the rescue phenotype. Rather, glutamine deficiency prevented the suppressive effect of the SFA palmitate on mitochondrial respiration and this phenotype was associated with protection from macrophage cell death. Together, these findings reveal that crosstalk between activation-induced metabolic reprogramming and the nutrient microenvironment can dramatically alter macrophage responses to inflammatory stimuli.

Obesity and diabetes are associated with macrophage dysfunction and increased NLRP3 inflammasome activation. Saturated fatty acids (FAs) are abundant in these metabolic disorders and have been associated with lysosome dysfunction and inflammasome activation in macrophages. However, the interplay between cellular metabolic pathways and lipid-induced toxicity in macrophages remains poorly understood. In this study, we investigated the role of the lipid metabolic enzyme long chain acyl-CoA synthetase (ACSL1) in primary macrophages. ACSL1 is upregulated in TLR4activated macrophages via a TIR (toll/IL-1R) domain-containing adapter inducing IFN-(TRIF)dependent pathway, and knockout of this enzyme decreased NLRP3 inflammasome activation.The mechanism of this response was not related to inflammasome priming, lipid uptake, or endoplasmic reticulum (ER) stress generation. Rather, ACSL1 was associated with mitochondria where it modulated fatty acid metabolism. The development of lysosome damage with palmitate exposure likely occurs via the formation of intracellular crystals. Herein, we provide evidence that loss of ACSL1 in macrophages decreases FA crystal formation thereby reducing lysosome damage and IL-1 release. These findings suggest that targeting lipid metabolic pathways in macrophages may be a strategy to reduce lipotoxity and to decrease pathologic inflammation in metabolic disease. K E Y W O R D Sdiabetes, inflammation, metabolism, monocyte/macrophage