Profound metabolic changes are characteristic of macrophages during classical activation and have been implicated in this phenotype. Here we demonstrate that nitric oxide (NO) produced by murine ...macrophages is responsible for TCA cycle alterations and citrate accumulation associated with polarization.
C tracing and mitochondrial respiration experiments map NO-mediated suppression of metabolism to mitochondrial aconitase (ACO2). Moreover, we find that inflammatory macrophages reroute pyruvate away from pyruvate dehydrogenase (PDH) in an NO-dependent and hypoxia-inducible factor 1α (Hif1α)-independent manner, thereby promoting glutamine-based anaplerosis. Ultimately, NO accumulation leads to suppression and loss of mitochondrial electron transport chain (ETC) complexes. Our data reveal that macrophages metabolic rewiring, in vitro and in vivo, is dependent on NO targeting specific pathways, resulting in reduced production of inflammatory mediators. Our findings require modification to current models of macrophage biology and demonstrate that reprogramming of metabolism should be considered a result rather than a mediator of inflammatory polarization.
Neutrophils are a vital component of immune protection, yet in cancer they may promote tumour progression, partly by generating reactive oxygen species (ROS) that disrupts lymphocyte functions. ...Metabolically, neutrophils are often discounted as purely glycolytic. Here we show that immature, c-Kit
neutrophils subsets can engage in oxidative mitochondrial metabolism. With limited glucose supply, oxidative neutrophils use mitochondrial fatty acid oxidation to support NADPH oxidase-dependent ROS production. In 4T1 tumour-bearing mice, mitochondrial fitness is enhanced in splenic neutrophils and is driven by c-Kit signalling. Concordantly, tumour-elicited oxidative neutrophils are able to maintain ROS production and T cell suppression when glucose utilisation is restricted. Consistent with these findings, peripheral blood neutrophils from patients with cancer also display increased immaturity, mitochondrial content and oxidative phosphorylation. Together, our data suggest that the glucose-restricted tumour microenvironment induces metabolically adapted, oxidative neutrophils to maintain local immune suppression.
The importance of metabolism in macrophage function has been reported, but the in vivo relevance of the in vitro observations is still unclear. Here we show that macrophage metabolites are defined in ...a specific tissue context, and these metabolites are crucially linked to tissue-resident macrophage functions. We find the peritoneum to be rich in glutamate, a glutaminolysis-fuel that is exploited by peritoneal-resident macrophages to maintain respiratory burst during phagocytosis via enhancing mitochondrial complex-II metabolism. This niche-supported, inducible mitochondrial function is dependent on protein kinase C activity, and is required to fine-tune the cytokine responses that control inflammation. In addition, we find that peritoneal-resident macrophage mitochondria are recruited to phagosomes and produce mitochondrially derived reactive oxygen species, which are necessary for microbial killing. We propose that tissue-resident macrophages are metabolically poised in situ to protect and exploit their tissue-niche by utilising locally available fuels to implement specific metabolic programmes upon microbial sensing.
Phagocytes are cells of the immune system that play important roles in phagocytosis, respiratory burst and degranulation—key components of innate immunity and response to infection. This diverse ...group of cells includes monocytes, macrophages, dendritic cells, neutrophils, eosinophils, and basophils—heterogeneous cell populations possessing cell and tissue‐specific functions of which cellular metabolism comprises a critical underpinning. Core functions of phagocytic cells are diverse and sensitive to alterations in environmental‐ and tissue‐specific nutrients and growth factors. As phagocytic cells adapt to these extracellular cues, cellular processes are altered and may contribute to pathogenesis. The considerable degree of functional heterogeneity among monocyte, neutrophil, and other phagocytic cell populations necessitates diverse metabolism. As we review our current understanding of metabolism in phagocytic cells, gaps are focused on to highlight the need for additional studies that hopefully enable improved cell‐based strategies for counteracting cancer and other diseases.
Review on the recent advances and current understanding of how phagocytic cells adapt to meet niche‐specific metabolic demands.
Fibrosis in response to tissue damage or persistent inflammation is a pathological hallmark of many chronic degenerative diseases. By using a model of acute peritoneal inflammation, we have examined ...how repeated inflammatory activation promotes fibrotic tissue injury. In this context, fibrosis was strictly dependent on interleukin-6 (IL-6). Repeat inflammation induced IL-6-mediated T helper 1 (Th1) cell effector commitment and the emergence of STAT1 (signal transducer and activator of transcription-1) activity within the peritoneal membrane. Fibrosis was not observed in mice lacking interferon-γ (IFN-γ), STAT1, or RAG-1. Here, IFN-γ and STAT1 signaling disrupted the turnover of extracellular matrix by metalloproteases. Whereas IL-6-deficient mice resisted fibrosis, transfer of polarized Th1 cells or inhibition of MMP activity reversed this outcome. Thus, IL-6 causes compromised tissue repair by shifting acute inflammation into a more chronic profibrotic state through induction of Th1 cell responses as a consequence of recurrent inflammation.
•Repeated acute resolving inflammation leads to excessive tissue damage•IL-6 regulates profibrotic IFN-γ-secreting T cells•IFN-γ increases detrimental STAT1 signaling in stromal tissue•STAT1 activity alters homeostatic control of extracellular matrix to promote fibrosis
Neutrophils are granulocytes with essential antimicrobial effector functions and short lifespans. During infection or sterile inflammation, emergency granulopoiesis leads to release of immature ...neutrophils from the bone marrow, serving to boost circulating neutrophil counts. Steady state and emergency granulopoiesis are incompletely understood, partly due to a lack of genetically amenable models of neutrophil development.
We optimised a method for ex vivo production of human neutrophils from CD34
haematopoietic progenitors. Using flow cytometry, we phenotypically compared cultured neutrophils with native neutrophils from donors experiencing emergency granulopoiesis, and steady state neutrophils from non-challenged donors. We carry out functional and proteomic characterisation of cultured neutrophils and establish genome editing of progenitors.
We obtain high yields of ex vivo cultured neutrophils, which phenotypically resemble immature neutrophils released into the circulation during emergency granulopoiesis. Cultured neutrophils have similar rates of ROS production and bacterial killing but altered degranulation, cytokine release and antifungal activity compared to mature neutrophils isolated from peripheral blood. These differences are likely due to incomplete synthesis of granule proteins, as demonstrated by proteomic analysis.
Ex vivo cultured neutrophils are genetically tractable via genome editing of precursors and provide a powerful model system for investigating the properties and behaviour of immature neutrophils.
The objective list theory of well‐being holds that a plurality of basic objective goods directly benefit people. These can include goods such as loving relationships, meaningful knowledge, autonomy, ...achievement, and pleasure. The objective list theory is pluralistic (it does not identify an underlying feature shared by these goods) and objective (the basic goods benefit people independently of their reactive attitudes toward them). In this paper, I discuss the structure of this theory and show how it is supported by people's considered judgments. I then respond to three objections. First, I argue that there is no conceptual reason to favor a monistic theory of well‐being over a pluralistic one (such as the objective list theory). Second, I argue that states of affairs can benefit people even though they hold no positive reactive attitudes toward them. And, third, I argue that objective list theorists can identify a fairly‐determinate list of basic goods.
What, if anything, directly detracts from well-being? Objective list theorists affirm basic goods such as knowledge, friendship, and achievement, but it is less clear what they should say about ...opposing bads. In this paper, I argue that false beliefs, unhealthy relationships, and failed projects are not basic bads and do not directly detract from well-being. They can have bad effects or elements, or block the realization of basic goods, but do not themselves carry negative weight with respect to well-being. This is shown by comparing cases where these bads are present and absent, examining their relation to negative overall well-being, and considering the role of these bads in the pursuit of positive goods.
Antimicrobial host defense is dependent on the rapid recruitment of inflammatory cells to the site of infection, the elimination of invading pathogens, and the efficient resolution of inflammation ...that minimizes damage to the host. The peritoneal cavity provides an accessible and physiologically relevant system where the delicate balance of these processes may be studied. Here, we describe murine models of peritoneal inflammation that enable studies of competent antimicrobial immunity and inflammation-associated tissue damage as a consequence of recurrent bacterial challenge. The inflammatory hallmarks of these models reflect the clinical and molecular features of peritonitis seen in renal failure patients on peritoneal dialysis. The development of these models relies on the preparation of a cell-free supernatant derived from an isolate of Staphylococcus epidermidis (termed SES). Intraperitoneal administration of SES induces a Toll-like receptor 2-driven acute inflammatory response that is characterized by an initial transient influx of neutrophils that are replaced by a more sustained recruitment of mononuclear cells and lymphocytes. Adaptation of this model using a repeated administration of SES allows investigations into the development of adaptive immunity and the hallmarks associated with tissue remodelling and fibrosis. These models are therefore clinically relevant and provide exciting opportunities to study innate and adaptive immunity and the response of the stromal tissue compartment to bacterial infection and the ensuing inflammatory reaction.
Peptidylarginine deiminase 4 (PAD4) is a key regulator of inflammation but its function in infections remains incompletely understood. We investigate PAD4 in the context of malaria and demonstrate a ...role in regulation of immune cell trafficking and chemokine production. PAD4 regulates liver immunopathology by promoting neutrophil trafficking in a Plasmodium chabaudi mouse malaria model. In human macrophages, PAD4 regulates expression of CXCL chemokines in response to stimulation with TLR ligands and P. falciparum. Using patient samples, we show that CXCL1 may be a biomarker for severe malaria. PAD4 inhibition promotes disease tolerance and may represent a therapeutic avenue in malaria.
Graphical
PAD4 promotes malaria immunopathology by regulating chemokine production in macrophages and enhancing recruitment of inflammatory cells.
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