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Principal Investigator: Chuanfu Li
Organization: EAST TENNESSEE STATE UNIVERSITY
Fiscal Year: 2024
Award: $576,326
Funding agency: National Institute of Allergy and Infectious Diseases
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.
Terms: <Address><Amphoterin><Amphoterin Gene><Bacteria><Basal Transcription Factor><Basal transcription factor genes><Biological Function><Biological Process><Cell Aging><Cell Cycle Arrest><Cell Senescence><Cellular Aging><Cellular Immune Function><Cellular Senescence><Cessation of life><Chromosomal Protein, Nonhistone, HMG1><Chromosomal Protein, Nonhistone, HMG1 Gene><Clinical Data><Data><Death><Death Rate><Development><Disease><Disorder><Dysfunction><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><FM1 Gene Product><Functional disorder><Gene Action Regulation><Gene Expression><Gene Expression Regulation><Gene Regulation><Gene Regulation Process><Gene Transcription><General Transcription Factor Gene><General Transcription Factors><Genetic Transcription><HMG-1><HMG-1 Gene><HMG-1 Protein><HMG1><HMG1 Gene><HMG3><HMG3 Gene><HMGB1><HMGB1 Protein><HMGB1 gene><Heparin-Binding Protein p30><High Mobility Group Box Protein 1><High Mobility Group Protein 1><High Mobility Group Protein 1 Gene><High-Mobility Group (Nonhistone Chromosomal) Protein 1><High-Mobility Group (Nonhistone Chromosomal) Protein 1 Gene><High-Mobility Group Box 1><High-Mobility Group Box 1 Gene><Histones><Immune Diseases><Immune Disorders><Immune Dysfunction><Immune System Diseases><Immune System Disorder><Immune System Dysfunction><Immune System and Related Disorders><Immune Targeting><Immune response><Immunodeficiency and Immunosuppression Disorders><Immunologic Diseases><Immunological Diseases><Immunological Dysfunction><Immunological System Dysfunction><Immunological response><Immunomodulation><Impairment><Infection><Inflammatory><Innovative Therapy><Life><Macrophage><Mediating><Mediator><Mice><Mice Mammals><Modification><Morbidity><Morbidity - disease rate><Murine><Mus><Mφ><Nonhistone Chromosomal Protein HGM1><Nonhistone Chromosomal Protein HGM1 Gene><Nuclear Translocation><Opportunistic Infections><Organ><Pathway interactions><Patients><Phagocytes><Phagocytic Cell><Phagocytosis><Phenotype><Physiopathology><Play><Pneumonia><Predisposition><Production><RNA Expression><RNA Seq><RNA sequencing><RNAseq><Replicative Senescence><Reporting><Risk><Role><SBP-1><SBP-1 Gene><Sepsis><Sepsis Syndrome><Severities><Sulfoglucuronyl Carbohydrate Binding Protein><Sulfoglucuronyl Carbohydrate Binding Protein Gene><Survivors><Susceptibility><Transcription><Transcription Factor Proto-Oncogene><Transcription factor genes><United States><Work><age associated><age correlated><age dependent><age linked><age related><age specific><amebocyte><blood infection><bloodstream infection><cellular targeting><developmental><epigenetically><host response><immune function><immune modulation><immune regulation><immune system response><immunologic reactivity control><immunomodulatory><immunoregulation><immunoregulatory><immunoresponse><improved><inhibitor><mortality><mortality rate><mortality ratio><non-histone protein><nonhistone protein><novel><p65><pathophysiology><pathway><response><senescence><senescence associated secretome><senescence associated secretory phenotype><senescent><sepsis patients><septic><septic patients><social role><survival outcome><transcription factor><transcriptome sequencing><transcriptomic sequencing>