Natural killer cells in sepsis: Friends or foes?

Wang, Fangjie; Cui, Yiqin; He, Dalin; Gong, Liang; Liang, Huaping

doi:10.3389/fimmu.2023.1101918

Cited by 8 publications

(6 citation statements)

References 181 publications

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“…The role of NK cells in sepsis is currently a subject of controversy within the scientific community. Some scholars suggest that the conflicting conclusions observed in various studies may be attributed to the varying states of the disease (38). Research conducted by Rubio et al has elucidated a notable upsurge in the cytotoxic capabilities of NK cells during the incipient stages of sepsis (39).…”

Section: Discussionmentioning

confidence: 99%

The Relationship Between Circulating Immune Cell Phenotypes and Sepsis: A Mendelian Randomization Study

Liu,

Zhou

et al. 2024

Shock

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Objective The role of immune cells in sepsis remains unclear, and there is some controversy. Here, we aim to systematically assess whether distinct immune cell phenotypes impact the susceptibility to sepsis. Methods In this study, we harnessed publicly available summary-level data from genome-wide association studies (GWAS). The selection of genetic variations strongly associated with 731 phenotypes of circulating immune cells served as instrumental variables (IVs). Using a two-sample Mendelian randomization (MR) analysis, we investigated the relationships between different immunophenotypes and the occurrence of sepsis, as well as the 28-day mortality. The MR study utilized the Inverse Variance Weighting (IVW) method as the main analytical approach. Additionally, we incorporated four other MR methods for supplementary causal inference, including Weighted Median (WME), MR-Egger regression, Simple Mode, and Weighted Mode. Furthermore, the robustness of the results was affirmed through multiple sensitivity analyses. Results The results of the IVW method indicated that a total of 36 immunophenotypes are associated with the risk of sepsis. we also identified 34 immunophenotypes with a causal association with the 28-day mortality. Interestingly, before multiple testing corrections, 11 immunophenotypes were determined to have consistent causal relationships with both the occurrence of sepsis and the 28-day mortality. Notably, after False Discovery Rate (FDR) correction, four immunophenotypes were found to be significantly correlated with susceptibility to sepsis: CD45RA− CD4+ %CD4 + (OR = 1.355, 95% CI = 1.139 ~ 1.611, P < 0.001, P FDR = 0.192), HLA DR on HLA DR+ NK(OR = 0.818, 95% CI = 0.726 ~ 0.922, P = 0.001, PFDR = 0.192), IgD+ CD24+ %B cell(OR = 0.626, 95% CI = 0.473 ~ 0.828, P = 0.001, PFDR = 0.192), TD DN (CD4 − CD8−) AC(OR = 0.655, 95% CI = 0.510 ~ 0.840, P < 0.001, PFDR = 0.192). Following FDR correction, only one immunophenotype was confirmed to be negatively correlated with the 28-day mortality: CD39 on CD39+ CD8br(OR = 0.820, 95% CI = 0.737 ~ 0.912, P < 0.001, PFDR = 0.184). Conclusion This study, for the first time, has uncovered indicative evidence of a causal relationship between circulating immune cell phenotypes and varying degrees of sepsis through genetic means. These findings underscore the significance of immune cells in the pathogenesis of sepsis.

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Section: Discussionmentioning

confidence: 99%

The Relationship Between Circulating Immune Cell Phenotypes and Sepsis: A Mendelian Randomization Study

Liu,

Zhou

et al. 2024

Shock

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“…Dendritic cells can carry molecules recognized as antigens and present them to T lymphocytes, which activate specific immune responses [ 35 ]. Natural killer cells can secrete large amounts of cytotoxic substances and various chemokines that attract other inflammatory cells to the site of infection [ 36 ]. Similarly, colitis in mice involves the cooperation of various immune cells, including neutrophils, macrophages, dendritic cells, and T cells [ 37 ].…”

Section: Discussionmentioning

confidence: 99%

α-Aminobutyric Acid Constrains Macrophage-Associated Inflammatory Diseases through Metabolic Reprogramming and Epigenetic Modification

Yan

Yuan

et al. 2023

IJMS

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Metabolites play critical roles in macrophage polarization and in their function in response to infection and inflammation. α-aminobutyric acid (AABA), a non-proteinogenic amino acid which can be generated from methionine, threonine, serine, and glycine, has not been studied extensively in relation to macrophage polarization and function. In this study, we aimed to investigate the immunomodulatory function of AABA in regulating M1 macrophage polarization and function in vitro and in vivo. We stimulated bone-marrow-derived macrophages with lipopolysaccharide (LPS) to generate M1 macrophages. Subsequently, we induced sepsis and colitis in mice, followed by treatment with AABA. We then analyzed the samples using ELISA, real-time PCR, Western blotting, flow cytometry, and histopathological analysis to evaluate cytokine secretion, inflammatory gene expression, macrophage activation, disease progression, and inflammation severity. Additionally, metabolomic and chromatin immunoprecipitation-qPCR were conducted to investigate the function of AABA on metabolic reprogramming and epigenetic modifications of M1 macrophages. Our results revealed that AABA inhibited M1 macrophage polarization and function, which led to prolonged survival in septic mice and reduced disease severity in colitis mice. Mechanically, AABA promoted oxidative phosphorylation (OXPHOS) and glutamine and arginine metabolism while inhibiting glycolysis. Moreover, AABA could increase the occupancy of trimethylation of histone H3K27 at the promoter regions of M1 macrophage-associated inflammatory genes, which contributed to the inhibition of M1 macrophage polarization. These findings suggest that AABA may have therapeutic potential for inflammatory diseases by regulating macrophage polarization and function through metabolic and epigenetic pathways.

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“…NK cells originate from a similar lineage with innate lymphoid cells but lack the expression of specific T‐cell receptors. This feature benefits rapid, non‐specific immune response for NK cells to intracellular pathogens intrusion ( 42 ). In the hyper-inflammatory phase of sepsis, excessive derivation of IFN-γ leads to anomalies in NK cell activation and can initiate cytokine storms through a positive feedback loop, causing severe organ damage ( 42 ).…”

Section: Violent Restructuring Of Immune Cellsmentioning

confidence: 99%

“…This feature benefits rapid, non‐specific immune response for NK cells to intracellular pathogens intrusion ( 42 ). In the hyper-inflammatory phase of sepsis, excessive derivation of IFN-γ leads to anomalies in NK cell activation and can initiate cytokine storms through a positive feedback loop, causing severe organ damage ( 42 ). One of NK cells’ defects is the main cytotoxic dysfunction, another is the shrinkage of IFN‐γ rendering post-septic patients more susceptible to a second attack ( 42 ).…”

Section: Violent Restructuring Of Immune Cellsmentioning

confidence: 99%

“…In the hyper-inflammatory phase of sepsis, excessive derivation of IFN-γ leads to anomalies in NK cell activation and can initiate cytokine storms through a positive feedback loop, causing severe organ damage ( 42 ). One of NK cells’ defects is the main cytotoxic dysfunction, another is the shrinkage of IFN‐γ rendering post-septic patients more susceptible to a second attack ( 42 ). Tregs mediate NK cells’ tolerance in sepsis and increased PD-L1 in NK cells contributes to the poor outcome of septic patients ( 27 , 43 ).…”

Section: Violent Restructuring Of Immune Cellsmentioning

confidence: 99%

See 1 more Smart Citation

The potential immunological mechanisms of sepsis

Zhang,

Yuan

et al. 2024

Front. Immunol.

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Sepsis is described as a life-threatening organ dysfunction and a heterogeneous syndrome that is a leading cause of morbidity and mortality in intensive care settings. Severe sepsis could incite an uncontrollable surge of inflammatory cytokines, and the host immune system's immunosuppression could respond to counter excessive inflammatory responses, characterized by the accumulated anti-inflammatory cytokines, impaired function of immune cells, over-proliferation of myeloid-derived suppressor cells and regulatory T cells, depletion of immune effector cells by different means of death, etc. In this review, we delve into the underlying pathological mechanisms of sepsis, emphasizing both the hyperinflammatory phase and the associated immunosuppression. We offer an in-depth exploration of the critical mechanisms underlying sepsis, spanning from individual immune cells to a holistic organ perspective, and further down to the epigenetic and metabolic reprogramming. Furthermore, we outline the strengths of artificial intelligence in analyzing extensive datasets pertaining to septic patients, showcasing how classifiers trained on various clinical data sources can identify distinct sepsis phenotypes and thus to guide personalized therapy strategies for the management of sepsis. Additionally, we provide a comprehensive summary of recent, reliable biomarkers for hyperinflammatory and immunosuppressive states, facilitating more precise and expedited diagnosis of sepsis.

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Natural killer cells in sepsis: Friends or foes?

Cited by 8 publications

References 181 publications

The Relationship Between Circulating Immune Cell Phenotypes and Sepsis: A Mendelian Randomization Study

The Relationship Between Circulating Immune Cell Phenotypes and Sepsis: A Mendelian Randomization Study

α-Aminobutyric Acid Constrains Macrophage-Associated Inflammatory Diseases through Metabolic Reprogramming and Epigenetic Modification

The potential immunological mechanisms of sepsis

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