Thursday, May 2, 2024
5/2/2024
Sepsis represents a life-threatening disorder caused by a dysregulated host response. Sepsis survivors frequently have long-term immune dysfunction that contributes to high mortality from opportunistic infections. Clinical data shows that lactate levels strongly and positively correlate with severity, morbidity and mortality in sepsis5-8. It is unclear whether lactate contributes to sepsis impaired immune response and susceptibility to subsequent infection. To address this important question, we performed preliminary studies and observed that enhanced lactate levels markedly increased mortality. We also observed that lactate suppresses macrophage phagocytic function during sepsis. Our findings suggest that lactate exerts a previously unknown biological function contributing to the mortality of sepsis and re-infection of sepsis survivors. Cellular senescence is a fundamental mechanism of age-related organ dysfunction. Our RNA-seq and other preliminary data shows that lactate markedly induces macrophage senescence during sepsis. our preliminary data also shows that splenic macrophage senescence is significantly greater in macrophage specific YAP/TAZ deficient (mYAP/TAZ-/-) sham and septic mice than in WT controls. Our finding suggests that YAP is required for the protection against cellular senescence during sepsis. Interestingly, we found that lactate induces lactylation of YAP. We reported that lactate induces HMGB1 lactylation in macrophages25, suggesting that lactate could induce lactylation of non-histone proteins. Indeed, we made a novel observation in our preliminary studies that lactate induces Keap1 lactylation and increases Nrf2 activation. Keap1 is an important suppressor for activation of Nrf2 to upregulate the expression of genes related to suppressive Immune responses. Our findings indicate that lactate alters macrophage immune response during sepsis that may be mediated by promoting macrophage senescence and inducing lactylation of important transcription factors and co-effectors. Based on our novel findings, we hypothesize that lactate is a novel endogenous mediator which contributes to impaired macrophage immune function during sepsis via lactylation of transcription factors and effectors and promotion of cellular senescence. To critically evaluate this hypothesis, we propose three specific aims. Specific aim 1. Investigate the role of lactylation of YAP/TAZ in macrophage immune dysfunction during sepsis. Specific aim 2. Define the role of Keap1 lactylation and Nrf2 activation in macrophage immune dysfunction during sepsis. Specific aim 3. Investigate whether lactate promoted senescence of macrophages will contribute to impaired macrophage immune function during sepsis. Successful completion of the proposed studies will result in a wealth of new and novel data showing that lactate plays an important role in the regulation of immune responses during sepsis.
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