Macrophages are cells of the innate immune system that regulate the maintenance of tissue homeostasis, host defense during pathogen infection, and tissue repair in response to tissue injury. Recent ...studies indicate that macrophage functions are influenced by cellular metabolism, including lipid metabolism. Here, we review how macrophage lipid metabolism can be dynamically altered in different physiological and pathophysiological contexts and the key regulators involved. We also describe how alterations in lipid metabolism are integrated with the signaling pathways that specify macrophage functions, allowing for coordinated control of macrophage biology. Finally, we discuss how dysregulated lipid metabolism contributes to perturbed macrophage functions in settings such as atherosclerosis and pathogen infections.
Macrophages have diverse roles depending on the setting. They maintain tissue homeostasis at steady state, and can be activated to assume new, context-dependent functions in response to infection, metabolic stress, and tissue damage.Lipid metabolism has a key role in regulating macrophage functions. Signals that drive macrophage activation (e.g., to an inflammatory state that regulates host defense) impinge on metabolic-sensing pathways to coordinate shifts in lipid metabolism.Lipids are a source of energy for macrophages, and provide precursors for bioactive lipids and components of cellular membranes. Lipids also regulate signal transduction and gene regulation during macrophage activation.Dysregulated lipid metabolism is implicated in aberrant macrophage functions, for example, in atherosclerosis and obesity or in certain intracellular infections.
Inflammasomes are intracellular sensors that couple detection of pathogens and cellular stress to activation of Caspase-1, and consequent IL-1β and IL-18 maturation and pyroptotic cell death. Here, ...we show that the absent in melanoma 2 (AIM2) and nucleotidebinding oligomerization domain-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasomes trigger Caspase-1-dependent mitochondrial damage. Caspase-1 activates multiple pathways to precipitate mitochondrial disassembly, resulting in mitochondrial reactive oxygen species (ROS) production, dissipation of mitochondrial membrane potential, mitochondrial permeabilization, and fragmentation of the mitochondrial network. Moreover, Caspase-1 inhibits mitophagy to amplify mitochondrial damage, mediated in part by cleavage of the key mitophagy regulator Parkin. In the absence of Parkin activity, increased mitochondrial damage augments pyroptosis, as indicated by enhanced plasma membrane permeabilization and release of danger-associated molecular patterns (DAMPs). Therefore, like other initiator caspases, Caspase-1 activation by inflammasomes results in mitochondrial damage.
The NLRP3 (nucleotide-binding domain, leucine-rich-repeat-containing family, pyrin domain-containing 3) inflammasome mediates production of inflammatory mediators, such as IL-1β and IL-18, and as ...such is implicated in a variety of inflammatory processes, including infection, sepsis, autoinflammatory diseases, and metabolic diseases. The proximal steps in NLRP3 inflammasome activation are not well understood. Here we elucidate a critical role for Ca ²⁺ mobilization in activation of the NLRP3 inflammasome by multiple stimuli. We demonstrate that blocking Ca ²⁺ mobilization inhibits assembly and activation of the NLRP3 inflammasome complex, and that during ATP stimulation Ca ²⁺ signaling is pivotal in promoting mitochondrial damage. C/EPB homologous protein, a transcription factor that can modulate Ca ²⁺ release from the endoplasmic reticulum, amplifies NLRP3 inflammasome activation, thus linking endoplasmic reticulum stress to activation of the NLRP3 inflammasome. Our findings support a model for NLRP3 inflammasome activation by Ca ²⁺-mediated mitochondrial damage.
Highlights • The NLRP3 inflammasome is activated by mitochondrial destabilization and dysfunction. • Recognition of mtDNA and externalized cardiolipin by the NLRP3 inflammasome may be direct. • Ca2+ ...is mobilized in many settings of NLRP3 inflammasome activation. • Intercepting Ca2+ mobilization inhibits inflammasome activation. • Ca2+ may trigger mitochondrial destabilization leading to NLRP3 inflammasome activation.
Constitutive cell-autonomous immunity in metazoans predates interferon-inducible immunity and comprises primordial innate defense. Phagocytes mobilize interferon-inducible responses upon engagement ...of well-characterized signaling pathways by pathogen-associated molecular patterns (PAMPs). The signals controlling deployment of constitutive cell-autonomous responses during infection have remained elusive. Vita-PAMPs denote microbial viability, signaling the danger of cellular exploitation by intracellular pathogens. We show that cyclic-di-adenosine monophosphate in live Gram-positive bacteria is a vita-PAMP, engaging the innate sensor stimulator of interferon genes (STING) to mediate endoplasmic reticulum (ER) stress. Subsequent inactivation of the mechanistic target of rapamycin mobilizes autophagy, which sequesters stressed ER membranes, resolves ER stress, and curtails phagocyte death. This vita-PAMP-induced ER-phagy additionally orchestrates an interferon response by localizing ER-resident STING to autophagosomes. Our findings identify stress-mediated ER-phagy as a cell-autonomous response mobilized by STING-dependent sensing of a specific vita-PAMP and elucidate how innate receptors engage multilayered homeostatic mechanisms to promote immunity and survival after infection.
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•Live Gram-positive bacteria cause ER stress, mTORC1 inactivation, and ER-phagy•ER-phagy controls the augmented interferon response to live Gram-positive bacteria•ER-phagy resolves ER stress and rescues phagocytes from death upon infection•STING senses c-di-AMP as a vita-PAMP to drive ER-phagy and interferon production
Detection of live bacteria through STING triggers ER-phagy and resolution of cellular stress, allowing cells to deal with the threat and remain viable and functional.
Macrophages are able to polarize to proinflammatory M1 or alternative M2 states with distinct phenotypes and physiological functions. How metabolic status regulates macrophage polarization remains ...not well understood, and here we examine the role of mTOR (mechanistic target of rapamycin), a central metabolic pathway that couples nutrient sensing to regulation of metabolic processes. Using a mouse model in which myeloid lineage-specific deletion of Tsc1 (Tsc1(Δ/Δ)) leads to constitutive mTOR complex 1 (mTORC1) activation, we find that Tsc1(Δ/Δ) macrophages are refractory to IL-4-induced M2 polarization, but produce increased inflammatory responses to proinflammatory stimuli. Moreover, mTORC1-mediated downregulation of Akt signalling critically contributes to defective polarization. These findings highlight a key role for the mTOR pathway in regulating macrophage polarization, and suggest how nutrient sensing and metabolic status could be 'hard-wired' to control of macrophage function, with broad implications for regulation of type 2 immunity, inflammation and allergy.
Macrophage activation/polarization to distinct functional states is critically supported by metabolic shifts. How polarizing signals coordinate metabolic and functional reprogramming, and the ...potential implications for control of macrophage activation, remains poorly understood. Here we show that IL-4 signaling co-opts the Akt-mTORC1 pathway to regulate Acly, a key enzyme in Ac-CoA synthesis, leading to increased histone acetylation and M2 gene induction. Only a subset of M2 genes is controlled in this way, including those regulating cellular proliferation and chemokine production. Moreover, metabolic signals impinge on the Akt-mTORC1 axis for such control of M2 activation. We propose that Akt-mTORC1 signaling calibrates metabolic state to energetically demanding aspects of M2 activation, which may define a new role for metabolism in supporting macrophage activation.
While M1 macrophages are highly pro-inflammatory and microbicidal, M2 macrophages and the related tu- mor associated macrophages （TAMs） regulate tissue remodeling and angio- genesis and can display ...immunomod- ulatory activity. In July issue of Cell Research, Zhang et aL show that ROS production, critical for the activation and functions of M1 macrophages, is necessary for the differentiation of M2 macrophages and TAMs, and that antioxidant therapy blocks TAM differentiation and tumorigenesis in mouse models of cancer.
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