# Novel Role of Lactate in Sepsis Impaired Immune Function

> **NIH NIH R01** · EAST TENNESSEE STATE UNIVERSITY · 2024 · $576,326

## Abstract

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.

## Key facts

- **NIH application ID:** 10812035
- **Project number:** 1R01AI174020-01A1
- **Recipient organization:** EAST TENNESSEE STATE UNIVERSITY
- **Principal Investigator:** Chuanfu Li
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $576,326
- **Award type:** 1
- **Project period:** 2023-12-12 → 2028-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10812035

## Citation

> US National Institutes of Health, RePORTER application 10812035, Novel Role of Lactate in Sepsis Impaired Immune Function (1R01AI174020-01A1). Retrieved via AI Analytics 2026-09-25 from https://api.ai-analytics.org/grant/nih/10812035. Licensed CC0.

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