# Pathogenesis of sepsis-induced dysfunction of innate immunity

> **NIH VA I01** · JESSE BROWN VA MEDICAL CENTER · 2020 · —

## Abstract

Our long-term goal is to study molecular mechanisms underlying pathogenesis of sepsis, a potentially
life-threatening illness caused by severe traumatic injury and trauma infections. Sepsis is the most costly
condition for VA hospitals to treat. When sepsis becomes severe, it has a high mortality rate even with
appropriate care. Sepsis is associated with overwhelming inflammatory response and dysregulation of innate
immunity, which can lead to persistent inflammation and multiple organ failure. The mechanisms by which this
pathophysiological problem occurs remain unknown. Evidence shows that macrophages play an important
role in the innate immune response. They undergo polarization to M1 phenotype (i.e. inflammatory
macrophages) and M2 phenotype (i.e. anti-inflammatory macrophages) in inflammation depending on local
environments. Currently, the exact phenotype of macrophages in inflammatory sites during sepsis is not clear.
The molecular mechanisms underlying polarization of macrophages in sepsis is unknown. Furthermore, the
impact of macrophage polarization in pathogenesis of sepsis-associated immune dysregulation and tissue
injury has not been elucidated. Thus, we will focus on filling these knowledge gaps in this project. In
preliminary studies, we found that polymicrobial sepsis is associated with increase in M1-like macrophages in
mouse lungs. M1 macrophage activation is coupled with increase in levels of Sirt6, a key regulator for cell
metabolism. Furthermore, loss-of-function and gain-of-function studies revealed the link between Sirt6 and M1
macrophage activation. Therefore, we will study whether Sirt6 plays an important role in septic insult-induced
M1 macrophage activation and tissue injury, and if so, we will study the molecular mechanism by which Sirt6
promotes M1 macrophage activation. To this end, we will execute the following studies. Specific Aim 1 will
determine the role of Sirt6 in M1 macrophage activation under cytokine-stimulation and septic condition.
Specific Aim 2 will study how Sirt6 potentiates M1 macrophage activation in inflammation. Specific Aim 3 will
examine whether Sirt6-associated signal axis in macrophages impacts pathogenesis of sepsis. Achievement
of these specific aims will provide novel information regarding how severe inflammation in sepsis causes
imbalance of M1-M2 macrophage activation, which may ultimately lead to development of strategies for
maintaining macrophage homeostasis in patients with sepsis. Data derived from the proposed work will
expand our knowledge on mechanisms underlying progression of sepsis to persistent inflammation and
multiple organ injury. Sepsis is a common and serious complication for surgery patients in the Department of
Veterans Affairs Healthcare System. Thus, the subject matter of this proposal is timely important and links to
clinical application for management of VA patients with critical illness.

## Key facts

- **NIH application ID:** 9898295
- **Project number:** 5I01BX004120-03
- **Recipient organization:** JESSE BROWN VA MEDICAL CENTER
- **Principal Investigator:** Xiao-Di Tan
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2018-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9898295

## Citation

> US National Institutes of Health, RePORTER application 9898295, Pathogenesis of sepsis-induced dysfunction of innate immunity (5I01BX004120-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9898295. Licensed CC0.

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