Resolving sepsis-induced immunoparalysis via trained immunity by targeting interleukin-4 to myeloid cells

Schrijver, David P.; Röring, Rutger J.; Deckers, Jeroen; Dreu, Anne de; Toner, Yohana C.; Prévot, Geoffrey; Priem, Bram; Munitz, Jazz; Nugraha, Eveline G.; Elsas, Yuri van; Azzun, Anthony; Anbergen, Tom; Groh, Laszlo; Becker, Anouk M. D.; Pérez-Medina, Carlos; Oosterwijk, Roderick S.; Novakovic, Boris; Moorlag, Simone J.C.F.M.; Jansen, Aron; Pickkers, Peter; Kox, Matthijs; Beldman, Thijs J.; Kluza, Ewelina; Leent, Mandy M. T. van; Teunissen, Abraham J. P.; Meel, Roy van der; Fayad, Zahi A.; Joosten, Leo A. B.; Fisher, Edward A.; Merkx, Maarten; Netea, Mihai G.; Mulder, Willem J. M.

doi:10.1038/s41551-023-01050-0

Cited by 27 publications

(7 citation statements)

References 47 publications

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“…Trained immunity improves innate responses to infection and is emerging as a key component of host directed therapies (HDT) and strategies to improve vaccine efficacy and the design of respiratory mucosal vaccines (26,27,(37)(38)(39). Both IFN-γ and IL-4 can induce trained immunity in murine and human macrophages (12,19,40,41). MDM trained with IFN-γ and LPS, and stimulated with Mtb had increased TNF in the acute activation phase of trained immunity (19), which we observed in IFN-γ primed MDM subsequently stimulated with Mtb.…”

Section: Discussionmentioning

confidence: 99%

Human airway macrophages are metabolically reprogrammed by IFN-γ resulting in glycolysis dependent functional plasticity

Cox,

Connolly,

Maoldomhnaigh

et al. 2024

Preprint

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Airway macrophages (AM) are the predominant immune cell in the lung and play a crucial role in preventing infection, making them a target for host directed therapy. Macrophage effector functions are associated with cellular metabolism. A knowledge gap remains in understanding metabolic reprogramming and functional plasticity of distinct human macrophage subpopulations, especially in lung resident AM. We examined tissue-resident AM and monocyte derived macrophages (MDM; as a model of blood derived macrophages) in their resting state and after priming with IFN-γ or IL-4 to model the Th1/Th2 axis in the lung. Human macrophages, regardless of origin, had a strong induction of glycolysis in response to IFN-γ or upon stimulation. IFN-γ significantly enhanced cellular energetics in both AM and MDM by upregulating both glycolysis and oxidative phosphorylation. Upon stimulation, AM do not decrease oxidative phosphorylation unlike MDM which shift to Warburg metabolism. IFN-γ priming promoted cytokine secretion in AM. Blocking glycolysis with 2-deoxyglucose significantly reduced IFN-γ driven cytokine production in AM, indicating that IFN-γ induces functional plasticity in human AM, which is mechanistically mediated by glycolysis. Directly comparing responses between macrophages, AM were more responsive to IFN-γ priming and dependent on glycolysis for cytokine secretion than MDM. Interestingly, TNF production was under the control of glycolysis in AM and not in MDM. MDM exhibited glycolysis-dependent upregulation of HLA-DR, CD40 and CD86, whereas IFN-γ upregulated HLA-DR and CD40 on AM independently of glycolysis. These data indicate that human AM are functionally plastic and respond to IFN-γ in a manner distinct from MDM. These data provide evidence that human AM are a tractable target for inhalable immunomodulatory therapies for respiratory diseases.

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Section: Discussionmentioning

confidence: 99%

Human airway macrophages are metabolically reprogrammed by IFN-γ resulting in glycolysis dependent functional plasticity

Cox,

Connolly,

Maoldomhnaigh

et al. 2024

Preprint

View full text Add to dashboard Cite

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“…While sepsis provides a pertinent analog for the systemic endotoxin exposure observed in SAM and a sepsis-like biomarker profile has been described among children recovering from SAM who die after hospital discharge ( 26 , 27 ), only one (0.01%) of our cohort of children with complicated SAM was septic at the time of blood sampling. Thus, improved understanding of how immune adaptations occur could support stratification of patients according to specific immunological risk factors, as has been trialed for immune hyper- versus hyporeactive states in septic patients ( 43 , 44 ).…”

Section: Discussionmentioning

confidence: 99%

Severe acute malnutrition promotes bacterial binding over proinflammatory cytokine secretion by circulating innate immune cells

Phiri,

Mutasa,

Rukobo

et al. 2023

Sci. Adv.

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Children with severe acute malnutrition (SAM) have high infectious mortality and morbidity, implicating defects in their immune defenses. We hypothesized that circulating innate immune cells from children (0 to 59 months) hospitalized with SAM in Zambia and Zimbabwe ( n = 141) have distinct capacity to respond to bacteria relative to adequately nourished healthy controls ( n = 92). SAM inpatients had higher neutrophil and monocyte Escherichia coli binding capacity but lower monocyte activation and proinflammatory mediator secretion in response to lipopolysaccharide or heat-killed Salmonella typhimurium than controls. Among SAM cases, wasting severity was negatively associated with cytokine secretion, children with HIV had lower monocyte activation, and the youngest children released the least myeloperoxidase upon stimulation. Inpatient bacterial binding capacity and monocyte activation were associated with higher odds of persistent SAM at discharge, a risk factor for subsequent mortality. Thus, SAM shifts innate immune cell function, favoring bacterial containment over proinflammatory activation, which may contribute to health deficits after discharge.

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“…118 Schrijver et al loaded the fusion protein of apolipoprotein A1 and IL-4 into lipid NPs and found these lipid NPs could overcome immunoparalysis in septic mice. 119 As an early discovered lipid NPs, liposomes were proposed as an effective drug-delivery system. Chen et al suggested that lanosterolcontaining liposomes (LAN-L) had anti-inflammatory effects in sepsis and reduced mortality in septic mice.…”

Section: How Nano-medicinal Materials Can Help Diagnose and Treat Sep...mentioning

confidence: 99%

How Extracellular Nano-Vesicles Can Play a Role in Sepsis? An Evidence-Based Review of the Literature

Jin,

Sun,

Yang

2023

IJN

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Sepsis is a systemic inflammatory reaction caused by infection. Severe sepsis can lead to multiple organ dysfunction, with a high incidence rate and mortality. The molecular pathogenesis of sepsis is complex and diverse. In recent years, with further study of the role of extracellular vesicles (EVs) in inflammatory diseases, it has been found that EVs play a dual role in the imbalance of inflammatory response in sepsis. Due to the great advantages such as lower toxicity, lower immunogenicity compared with stem cells and better circulation stability, EVs are increasingly used for the diagnosis and treatment of sepsis. The roles of EVs in the pathogenesis, diagnosis and treatment of sepsis were summarized to guide further clinical studies.

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Resolving sepsis-induced immunoparalysis via trained immunity by targeting interleukin-4 to myeloid cells

Cited by 27 publications

References 47 publications

Human airway macrophages are metabolically reprogrammed by IFN-γ resulting in glycolysis dependent functional plasticity

Human airway macrophages are metabolically reprogrammed by IFN-γ resulting in glycolysis dependent functional plasticity

Severe acute malnutrition promotes bacterial binding over proinflammatory cytokine secretion by circulating innate immune cells

How Extracellular Nano-Vesicles Can Play a Role in Sepsis? An Evidence-Based Review of the Literature

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