Macrophages in immunoregulation and therapeutics

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: May 22, 2023

Abstract Macrophages exist in various tissues, several body cavities, and around mucosal surfaces are a vital part of the innate immune system for host defense against many pathogens cancers. possess binary M1/M2 macrophage polarization settings, which perform central role an array tasks via intrinsic signal cascades and, therefore, must be precisely regulated. Many crucial questions about signaling modulation yet to uncovered. In addition, clinical importance tumor-associated macrophages is becoming more widely recognized as significant progress has been made understanding their biology. Moreover, they integral tumor microenvironment, playing regulation wide variety processes including angiogenesis, extracellular matrix transformation, cancer cell proliferation, metastasis, immunosuppression, resistance chemotherapeutic checkpoint blockade immunotherapies. Herein, we discuss signaling, mechanical stresses modulation, metabolic pathways, mitochondrial transcriptional, epigenetic regulation. Furthermore, have broadly extended traps essential roles autophagy aging regulating functions. discussed recent advances macrophages-mediated autoimmune diseases tumorigenesis. Lastly, targeted therapy portray prospective targets therapeutic strategies health diseases.

Language: Английский

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Krebs Cycle Reborn in Macrophage Immunometabolism

Annual Review of Immunology, Journal Year: 2020, Volume and Issue: 38(1), P. 289 - 313

Published: Jan. 27, 2020

A striking change has happened in the field of immunology whereby specific metabolic processes have been shown to be a critical determinant immune cell activation. Multiple receptor types rewire pathways as key part how they promote effector functions. Perhaps surprisingly for immunologists, Krebs cycle emerged central immunometabolic hub macrophage. During proinflammatory macrophage activation, there is an accumulation intermediates succinate and citrate, cycle–derived metabolite itaconate. These metabolites distinct nonmetabolic signaling roles that influence inflammatory gene expression. bioenergetic target cycle, electron transport chain, also becomes altered, generating reactive oxygen species from Complexes I III. Similarly, alternatively activated macrophages require α-ketoglutarate-dependent epigenetic reprogramming elicit anti-inflammatory In this review, we discuss these advances speculate on possibility targeting events therapeutically diseases.

Language: Английский

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The role of itaconate in host defense and inflammation

Journal of Clinical Investigation, Journal Year: 2022, Volume and Issue: 132(2)

Published: Jan. 17, 2022

Macrophages exposed to inflammatory stimuli including LPS undergo metabolic reprogramming facilitate macrophage effector function. This supports phagocytic function, cytokine release, and ROS production that are critical protective responses. The Krebs cycle is a central pathway within all mammalian cell types. In activated macrophages, distinct breaks in the regulate function through accumulation of several metabolites were recently shown have signaling roles immunity. One metabolite accumulates macrophages because disturbance itaconate, which derived from cis-aconitate by enzyme decarboxylase (ACOD1), encoded immunoresponsive gene 1 (Irg1). Review focuses on itaconate’s emergence as key immunometabolite with diverse immunity inflammation. These include inhibition succinate dehydrogenase (which controls levels succinate, multiple inflammation), glycolysis at will limit activation antiinflammatory transcription factors Nrf2 ATF3, NLRP3 inflammasome. Itaconate its derivatives effects preclinical models sepsis, viral infections, psoriasis, gout, ischemia/reperfusion injury, pulmonary fibrosis, pointing possible itaconate-based therapeutics for range diseases. intriguing continues yield fascinating insights into role host defense

Language: Английский

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Mitochondrial electron transport chain is necessary for NLRP3 inflammasome activation

Nature Immunology, Journal Year: 2022, Volume and Issue: 23(5), P. 692 - 704

Published: April 28, 2022

Abstract The NLRP3 inflammasome is linked to sterile and pathogen-dependent inflammation, its dysregulation underlies many chronic diseases. Mitochondria have been implicated as regulators of the through several mechanisms including generation mitochondrial reactive oxygen species (ROS). Here, we report that electron transport chain (ETC) complex I, II, III V inhibitors all prevent activation. Ectopic expression Saccharomyces cerevisiae NADH dehydrogenase (NDI1) or Ciona intestinalis alternative oxidase, which can complement functional loss I III, respectively, without ROS, rescued activation in absence endogenous function. Metabolomics revealed phosphocreatine (PCr), sustain ATP levels, a common metabolite diminished by ETC inhibitors. PCr depletion decreased levels Thus, sustains PCr-dependent ATP, but via ROS-independent mechanism.

Language: Английский

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Nitric Oxide in Macrophage Immunometabolism: Hiding in Plain Sight

Metabolites, Journal Year: 2020, Volume and Issue: 10(11), P. 429 - 429

Published: Oct. 26, 2020

Nitric Oxide (NO) is a soluble endogenous gas with various biological functions like signaling, and working as an effector molecule or metabolic regulator. In response to inflammatory signals, immune myeloid cells, macrophages, increase production of cytokines NO, which important for pathogen killing. Under these proinflammatory circumstances, called “M1”, macrophages undergo series changes including rewiring their tricarboxylic acid (TCA) cycle. Here, we review findings indicating that through its interaction heme non-heme metal containing proteins, together components the electron transport chain, not only regulator cell respiration, but also modulator intracellular metabolism. Moreover, diverse effects NO NO-derived reactive nitrogen species (RNS) involve precise interactions different targets depending on concentration, temporal, spatial restrictions. Although role in macrophage reprogramming has been evidence some time, current models have largely minimized importance. It has, therefore, hiding plain sight. A chemical properties past biochemical studies, recent publications, necessitates mechanisms TCA during stimulation must be re-imagined re-interpreted mechanistic results exposure. The revised model describe here incorporates many early regarding biochemistry brings out forefront immunometabolism.

Language: Английский

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More than just protein building blocks: how amino acids and related metabolic pathways fuel macrophage polarization

FEBS Journal, Journal Year: 2021, Volume and Issue: 288(12), P. 3694 - 3714

Published: Jan. 18, 2021

Macrophages represent the first line of defence in innate immune responses and additionally serve important functions for regulation host inflammation tissue homeostasis. The M1/M2 model describes two extremes macrophage polarization states, which can be induced by multiple stimuli, most notably LPS/IFN-γ IL-4/IL-13. Historically, expression genes encoding enzymes, use same amino acid as their substrate, iNOS ARG1, has been used to define classically activated M1 (iNOS) alternatively M2 (ARG1) macrophages. This 'arginine dichotomy' recently become a matter debate; however, parallel with emerging field immunometabolism there is accumulating evidence that these enzymes related metabolites are fundamentally involved intrinsic function. aim this review highlight recent advances biology specific focus on metabolism metabolic pathways: iNOS/ARG1 (arginine), TCA cycle OXPHOS (glutamine) well one-carbon (serine, glycine).

Language: Английский

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A small molecule G6PD inhibitor reveals immune dependence on pentose phosphate pathway

Nature Chemical Biology, Journal Year: 2020, Volume and Issue: 16(7), P. 731 - 739

Published: May 11, 2020

Language: Английский

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Itaconate inhibits TET DNA dioxygenases to dampen inflammatory responses

Nature Cell Biology, Journal Year: 2022, Volume and Issue: 24(3), P. 353 - 363

Published: March 1, 2022

Language: Английский

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Malonate Promotes Adult Cardiomyocyte Proliferation and Heart Regeneration

Circulation, Journal Year: 2021, Volume and Issue: 143(20), P. 1973 - 1986

Published: March 5, 2021

Neonatal mouse cardiomyocytes undergo a metabolic switch from glycolysis to oxidative phosphorylation, which results in significant increase reactive oxygen species production that induces DNA damage. These cellular changes contribute cardiomyocyte cell cycle exit and loss of the capacity for cardiac regeneration. The mechanisms regulate this have been relatively unexplored. Current evidence suggests elevated ischemic tissues occurs as result accumulation mitochondrial metabolite succinate during ischemia via dehydrogenase (SDH), is rapidly oxidized at reperfusion. Mutations SDH familial cancer syndromes demonstrated promote shift into glycolytic metabolism, suggesting potential role regulating metabolism. Whether activity state remains unclear.Here, we investigated inhibition regulation postnatal heart regeneration.Our demonstrate injection neonatal mice proliferation Our also shows by malonate treatment after birth extends window regeneration juvenile mice. Remarkably, extending adult myocardial infarction injury robust regenerative response within 4 weeks promoting revascularization. analysis dynamic metabolism.Inhibition promotes proliferation, revascularization, reprogramming. findings support potentially important new therapeutic approach human failure.

Language: Английский

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Macrophages are metabolically heterogeneous within the tumor microenvironment

Cell Reports, Journal Year: 2021, Volume and Issue: 37(13), P. 110171 - 110171

Published: Dec. 1, 2021

Macrophages are often prominently present in the tumor microenvironment, where distinct macrophage populations can differentially affect progression. Although metabolism influences function, studies on metabolic characteristics of ex vivo tumor-associated (TAM) subsets rather limited. Using transcriptomic and analyses, we now reveal that pro-inflammatory major histocompatibility complex (MHC)-IIhi TAMs display a hampered tricarboxylic acid (TCA) cycle, while reparative MHC-IIlo show higher oxidative glycolytic metabolism. both TAM rapidly exchange lactate high-lactate conditions, only use as an additional carbon source. Accordingly, supports TAMs, it decreases activity MHC-IIhi TAMs. Lactate subtly affects transcriptome increases L-arginine metabolism, enhances T cell suppressive capacity these Overall, our data uncover intricacies identify source functional regulator

Language: Английский

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