# Mechanisms of Tissue Immune Regulation in Sepsis and Local Infection

> **NIH NIH R35** · BRIGHAM AND WOMEN'S HOSPITAL · 2021 · $427,750

## Abstract

PROJECT SUMMARY/ABSTRACT
The immune system relies on the intrinsic ability of immune cells to respond to activating or inhibitory signals. In
the context of tissues, many of these signals are derived from neighboring non-immune cells sharing the same
immunomodulatory environment. Elucidating the links between spatial and functional cellular interactions
represents a major contemporary challenge, in particular to functional characterization of immunological
systems. Whereas several mechanisms of tissue-immune cell crosstalk have been established, this area has
not been systematically studied and the basic principles governing tissue immune regulation remain largely
unknown. Sepsis is a life-threatening condition characterized by profound dysregulation of both the immune
system and tissue homeostasis, ultimately converging on severe organ dysfunction. In particular, failure of
endothelial and epithelial barriers is a hallmark of sepsis-associated organ dysfunction and death. Recent
emerging paradigms describing sepsis pathogenesis highlight the interdependency of immune homeostasis and
tissue homeostasis and suggest that better understanding of mechanisms of tissue immune regulation is critical
for devising effective treatment strategies for sepsis. Despite the growing appreciation of the crosstalk between
cells and organs affected by sepsis, how tissues regulate antibacterial immunity in sepsis is poorly understood.
Our laboratory uses advanced mouse models and imaging platforms to study how tissues orchestrate the
immune response in the setting of immunity and inflammation. Through this proposal, we will develop and
validate novel concepts and platforms for interrogating 1) the liver sinusoid as an immunoregulatory unit in
sepsis; 2) epithelial inflammatory cytokines as guardians of the intestinal barrier in sepsis; and 3) intestinal
mesenchymal cells as critical modulators of local and systemic bacterial infection. Our studies will define the
immunological crosstalk established between tissue non-immune and immune cells and unravel the complex
multicellular mechanisms orchestrating tissue immune responses in bacterial sepsis. Ultimately, these studies
are aimed to establish the paradigm of tissue immune regulation in sepsis and advance the conceptual and
mechanistic understanding of the tissue-level immune pathways regulating antibacterial immunity.

## Key facts

- **NIH application ID:** 10136033
- **Project number:** 5R35GM133800-03
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Roni Nowarski
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $427,750
- **Award type:** 5
- **Project period:** 2019-07-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10136033

## Citation

> US National Institutes of Health, RePORTER application 10136033, Mechanisms of Tissue Immune Regulation in Sepsis and Local Infection (5R35GM133800-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10136033. Licensed CC0.

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