Extracellular citrate serves as a DAMP to activate macrophages and promote LPS-induced lung injury in mice

Duan, Jia‐Xi; Jiang, Huiling; Guan, Xin‐Xin; Zhang, Chenyu; Zhong, Wenjing; Zu, Cheng; Tao, Jia‐Hao; Yang, Jin‐Tong; Liu, Yu-Biao; Zhou, Yong; Chen, Ping; Yang, Huihui

doi:10.1016/j.intimp.2021.108372

Cited by 16 publications

(11 citation statements)

References 38 publications

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“…Furthermore, the malonylation response relies on citrate-derived metabolite malonyl-CoA production, which is an essential pro-inflammatory signal that promotes TNF translation and secretion by regulating glyceraldehyde 3-phosphate dehydrogenase (GAPDH) in response to inflammation induced by LPS ( 103 ). Furthermore, extracellular citrate may serve as a damage-associated molecular pattern (DAMP) and aggravate LPS-induced ALI by overactivating the NACHT, LRR, and PYD domain-containing protein 3 (NLRP3) inflammasome ( 104 ). Citrate and its metabolic intermediates play an important role in the M1 macrophage response, and their role in M2 macrophages needs to be further explored.…”

Section: Immunometabolism In Macrophage Polarizationmentioning

confidence: 99%

The role of immunometabolism in macrophage polarization and its impact on acute lung injury/acute respiratory distress syndrome

Wang

Zhang

et al. 2023

Front. Immunol.

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Lung macrophages constitute the first line of defense against airborne particles and microbes and are key to maintaining pulmonary immune homeostasis. There is increasing evidence suggesting that macrophages also participate in the pathogenesis of acute lung injury (ALI)/acute respiratory distress syndrome (ARDS), including the modulation of inflammatory responses and the repair of damaged lung tissues. The diversity of their functions may be attributed to their polarized states. Classically activated or inflammatory (M1) macrophages and alternatively activated or anti-inflammatory (M2) macrophages are the two main polarized macrophage phenotypes. The precise regulatory mechanism of macrophage polarization is a complex process that is not completely understood. A growing body of literature on immunometabolism has demonstrated the essential role of immunometabolism and its metabolic intermediates in macrophage polarization. In this review, we summarize macrophage polarization phenotypes, the role of immunometabolism, and its metabolic intermediates in macrophage polarization and ALI/ARDS, which may represent a new target and therapeutic direction.

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Section: Immunometabolism In Macrophage Polarizationmentioning

confidence: 99%

The role of immunometabolism in macrophage polarization and its impact on acute lung injury/acute respiratory distress syndrome

Wang

Zhang

et al. 2023

Front. Immunol.

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“…As mentioned above, citrate is enriched in LPS-treated macrophages. It has been recently found that enriched citrate can promote subsequent inflammatory responses ( Duan et al, 2021 ). Citrate has been shown to increase the expression of NLRP3 and pro-IL-1β and subsequently augment NLRP3 inflammasome activation.…”

Section: Key Enzymes and Metabolic Intermediates Emerging As Vital Pl...mentioning

confidence: 99%

“…Citrate has been shown to increase the expression of NLRP3 and pro-IL-1β and subsequently augment NLRP3 inflammasome activation. Abnormal NLRP3 inflammasome activation was considered to then aggravate lung injury induced by LPS( Duan et al, 2021 ).…”

Section: Key Enzymes and Metabolic Intermediates Emerging As Vital Pl...mentioning

confidence: 99%

Reprogramming Macrophage Metabolism and its Effect on NLRP3 Inflammasome Activation in Sepsis

Luo

Wang

2022

Front. Mol. Biosci.

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Sepsis, the most common life-threatening multi-organ dysfunction syndrome secondary to infection, lacks specific therapeutic strategy due to the limited understanding of underlying mechanisms. It is currently believed that inflammasomes play critical roles in the development of sepsis, among which NLRP3 inflammasome is involved to most extent. Recent studies have revealed that dramatic reprogramming of macrophage metabolism is commonly occurred in sepsis, and this dysregulation is closely related with the activation of NLRP3 inflammasome. In view of the fact that increasing evidence demonstrates the mechanism of metabolism reprogramming regulating NLRP3 activation in macrophages, the key enzymes and metabolites participated in this regulation should be clearer for better interpreting the relationship of NLRP3 inflammasome and sepsis. In this review, we thus summarized the detail mechanism of the metabolic reprogramming process and its important role in the NLRP3 inflammasome activation of macrophages in sepsis. This mechanism summarization will reveal the applicational potential of metabolic regulatory molecules in the treatment of sepsis.

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“…These immunologically active metabolites are referred to as immunometabolites. For example, Krebs cycle intermediates such as succinate and citrate have been found to accumulate upon activation of myeloid cells, an event that promotes increased gene expression levels proin ammatroy genes of (Duan et al, 2021;Tannahill et al, 2013), while accumulation of itaconate has suppressive effects in ammatory gene expression (Lampropoulou et al, 2016). Increases in the glycolytic end-product lactic acid, through the Warburg effect, is a hallmark of activated immune cells that in turn regulates in ammatory responses by affecting myeloid cell differentiation, NFkB signaling and in ammasome activation We have previously observed increased expression and activity of the in ammasome in a transdiagnostic cohort of severely ill individuals with psychiatric disorders.…”

Section: Introductionmentioning

confidence: 99%

Individuals with severe psychiatric disorders display altered pattern of plasma immunometabolites

Hylén

Särndahl

Bejerot

et al. 2023

Preprint

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Introduction Psychiatric disorders are common and significantly impact the quality of life. Inflammatory processes are proposed to contribute to the emergence of psychiatric disorders. In addition to inflammation, disturbances in metabolic pathways have been observed in individuals with different psychiatric disorders. A suggested key player in the interaction between inflammation and metabolism is the Nod-like receptor 3 (NLRP3) inflammasome, and NLRP3 is known to react to a number of specific metabolites. However, little is known about the interplay between these immunometabolites and the NLRP3 inflammasome in mental health disorders. Aim To assess the interplay between immunometabolites and inflammasome function in a transdiagnostic cohort of individuals with severe mental disorders. Methods Mass spectrometry-based analysis of selected immunometabolites, previously known to affect inflammasome function, were performed in plasma from low-functioning individuals with severe mental disorders (n=39) and sex and aged-matched healthy controls (n=39) using a transdiagnostic approach. Mann Whitney U test was used to test differences in immunometabolites between psychiatric patients and controls. To assess the relationship between inflammasome parameters, disease severity, and the immunometabolites, Spearman’s rank-order correlation test was used. Conditional logistic regression was used to control for potential confounding variables. Principal component analysis was performed to explore immunometabolic patterns. Results Among the selected immunometabolites (n=9), serine, glutamine, and lactic acid were significantly higher in the patient group compared to the controls. After adjusting for confounders, the differences remained significant for all three immunometabolites. No significant correlations were found between immunometabolites and disease severity. Conclusion Previous research on metabolic changes in mental disorders has not been conclusive. This study shows that severely ill patients have common metabolic perturbations. The changes in serine, glutamine, and lactic acid could constitute a direct contribution to the low-grade inflammation observed in severe psychiatric disorders.

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Extracellular citrate serves as a DAMP to activate macrophages and promote LPS-induced lung injury in mice

Cited by 16 publications

References 38 publications

The role of immunometabolism in macrophage polarization and its impact on acute lung injury/acute respiratory distress syndrome

The role of immunometabolism in macrophage polarization and its impact on acute lung injury/acute respiratory distress syndrome

Reprogramming Macrophage Metabolism and its Effect on NLRP3 Inflammasome Activation in Sepsis

Individuals with severe psychiatric disorders display altered pattern of plasma immunometabolites

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