Hypoxia Induces Macrophage tnfa Expression via Cyclooxygenase and Prostaglandin E2 in vivo

Lewis, Amy; Elks, Philip M.

doi:10.3389/fimmu.2019.02321

Cited by 39 publications

(34 citation statements)

References 68 publications

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“…Previously, others and us showed that following caudal fin fold amputation, zebrafish macrophages are recruited and acquire different functional phenotypes, very similar to that of mammals (8,9,(30)(31)(32). After injury, macrophages adopt a pro-inflammatory (M1-like) phenotype expressing proinflammatory cytokines such as tnfa, tnfb, il1b and il6 (8,(32)(33)(34)(35). While repair proceeds, macrophages switch toward noninflammatory phenotypes expressing cxcr4, ccr2 and tgfb1 (34).…”

Section: Introductionmentioning

confidence: 91%

Damage-Induced Calcium Signaling and Reactive Oxygen Species Mediate Macrophage Activation in Zebrafish

et al. 2021

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Immediately after a wound, macrophages are activated and change their phenotypes in reaction to danger signals released from the damaged tissues. The cues that contribute to macrophage activation after wounding in vivo are still poorly understood. Calcium signaling and Reactive Oxygen Species (ROS), mainly hydrogen peroxide, are conserved early wound signals that emanate from the wound and guide neutrophils within tissues up to the wound. However, the role of these signals in the recruitment and the activation of macrophages is elusive. Here we used the transparent zebrafish larva as a tractable vertebrate system to decipher the signaling cascade necessary for macrophage recruitment and activation after the injury of the caudal fin fold. By using transgenic reporter lines to track pro-inflammatory activated macrophages combined with high-resolutive microscopy, we tested the role of Ca²⁺ and ROS signaling in macrophage activation. By inhibiting intracellular Ca²⁺ released from the ER stores, we showed that macrophage recruitment and activation towards pro-inflammatory phenotypes are impaired. By contrast, ROS are only necessary for macrophage activation independently on calcium. Using genetic depletion of neutrophils, we showed that neutrophils are not essential for macrophage recruitment and activation. Finally, we identified Src family kinases, Lyn and Yrk and NF-κB as key regulators of macrophage activation in vivo, with Lyn and ROS presumably acting in the same signaling pathway. This study describes a molecular mechanism by which early wound signals drive macrophage polarization and suggests unique therapeutic targets to control macrophage activity during diseases.

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Section: Introductionmentioning

confidence: 91%

Damage-Induced Calcium Signaling and Reactive Oxygen Species Mediate Macrophage Activation in Zebrafish

et al. 2021

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“…There is a compelling list of publications describing the release of pro-inflammatory cytokines from cancer and hypoxic tissues ( Dinarello, 2006 ; Peyssonnaux et al, 2007 ; Popa et al, 2007 ; Heikkilä et al, 2008 ; Xing and Lu, 2016 ; Lewis and Elks, 2019 ; Kammerer et al, 2020 ). Recently, a transcriptomic meta-analysis of human cancers varying in degree of their pro-cachectic potential has been performed to identify new cachectic factors ( Freire et al, 2020 ).…”

Section: The Function Of Immune Cell-derived Sifs May Be Conserved Bementioning

confidence: 99%

Polarization of Macrophages in Insects: Opening Gates for Immuno-Metabolic Research

Bajgar

Krejčová

Doležal

2021

Front. Cell Dev. Biol.

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Insulin resistance and cachexia represent severe metabolic syndromes accompanying a variety of human pathological states, from life-threatening cancer and sepsis to chronic inflammatory states, such as obesity and autoimmune disorders. Although the origin of these metabolic syndromes has not been fully comprehended yet, a growing body of evidence indicates their possible interconnection with the acute and chronic activation of an innate immune response. Current progress in insect immuno-metabolic research reveals that the induction of insulin resistance might represent an adaptive mechanism during the acute phase of bacterial infection. In Drosophila, insulin resistance is induced by signaling factors released by bactericidal macrophages as a reflection of their metabolic polarization toward aerobic glycolysis. Such metabolic adaptation enables them to combat the invading pathogens efficiently but also makes them highly nutritionally demanding. Therefore, systemic metabolism has to be adjusted upon macrophage activation to provide them with nutrients and thus support the immune function. That anticipates the involvement of macrophage-derived systemic factors mediating the inter-organ signaling between macrophages and central energy-storing organs. Although it is crucial to coordinate the macrophage cellular metabolism with systemic metabolic changes during the acute phase of bacterial infection, the action of macrophage-derived factors may become maladaptive if chronic or in case of infection by an intracellular pathogen. We hypothesize that insulin resistance evoked by macrophage-derived signaling factors represents an adaptive mechanism for the mobilization of sources and their preferential delivery toward the activated immune system. We consider here the validity of the presented model for mammals and human medicine. The adoption of aerobic glycolysis by bactericidal macrophages as well as the induction of insulin resistance by macrophage-derived factors are conserved between insects and mammals. Chronic insulin resistance is at the base of many human metabolically conditioned diseases such as non-alcoholic steatohepatitis, atherosclerosis, diabetes, and cachexia. Therefore, revealing the original biological relevance of cytokine-induced insulin resistance may help to develop a suitable strategy for treating these frequent diseases.

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“…HIF‐1α knockouts have decreases in IFNγ [77], IL‐1β [51] and IL‐6 [51] leading to excess tissue damage and lower survival [46]. Early HIF‐1α stabilisation increases inflammatory factors leading to myeloid control of infection [48–50], while excessive HIF‐1α can lead to prolonged inflammation and larger TB lesions in later stage disease [51]. In the context of the fungal infection Candida albicans (yellow column), HIF‐1α knockout decreases pro‐inflammatory factors while increasing anti‐inflammatory IL‐10 leading to increased fungal survival [55].…”

Section: Upregulating Hif In Infectionsmentioning

confidence: 99%

“…During early infection, HIF‐1α stabilisation is beneficial for innate immune control of TB. In a zebrafish TB model, using the fish‐adapted pathogen and close genetic relative of Mtb, Mycobacterium marinum (Mm), Hif‐1α stabilisation increased myeloid production of Il‐1β, vital for decreasing bacterial burden via neutrophil nitric oxide (NO) production [48,49], alongside increasing pro‐inflammatory macrophage Tnfa production [50]. The HIF‐induced, host NO response has also shown to be important in a mouse model of TB infection, with HIF‐1α and iNOS in a positive feedback loop, balancing the inflammatory phenotype [51].…”

Section: Upregulating Hif In Infectionsmentioning

confidence: 99%

If it’s not one thing, HIF’s another: immunoregulation by hypoxia inducible factors in disease

2020

Self Cite

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Hypoxia‐inducible factors (HIFs) have emerged in recent years as critical regulators of immunity. Localised, low oxygen tension is a hallmark of inflamed and infected tissues. Subsequent myeloid cell HIF stabilisation plays key roles in the innate immune response, alongside emerging oxygen‐independent roles. Manipulation of regulatory proteins of the HIF transcription factor family can profoundly influence inflammatory profiles, innate immune cell function and pathogen clearance and, as such, has been proposed as a therapeutic strategy against inflammatory diseases. The direction and mode of HIF manipulation as a therapy are dictated by the inflammatory properties of the disease in question, with innate immune cell HIF reduction being, in general, advantageous during chronic inflammatory conditions, while upregulation of HIF is beneficial during infections. The therapeutic potential of targeting myeloid HIFs, both genetically and pharmacologically, has been recently illuminated in vitro and in vivo, with an emerging range of inhibitory and activating strategies becoming available. This review focuses on cutting edge findings that uncover the roles of myeloid cell HIF signalling on immunoregulation in the contexts of inflammation and infection and explores future directions of potential therapeutic strategies.

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Hypoxia Induces Macrophage tnfa Expression via Cyclooxygenase and Prostaglandin E2 in vivo

Cited by 39 publications

References 68 publications

Damage-Induced Calcium Signaling and Reactive Oxygen Species Mediate Macrophage Activation in Zebrafish

Damage-Induced Calcium Signaling and Reactive Oxygen Species Mediate Macrophage Activation in Zebrafish

Polarization of Macrophages in Insects: Opening Gates for Immuno-Metabolic Research

If it’s not one thing, HIF’s another: immunoregulation by hypoxia inducible factors in disease

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