# Inhibition of STAT3 and inflammatory cytokine production

> **NIH NIH R01** · HOSPITAL FOR SPECIAL SURGERY · 2021 · $445,000

## Abstract

Macrophages play important roles in tissue homeostasis, host defense, response to injury, tissue
repair, and resolution of inflammation. The long term goals of this project are to understand how
macrophage functional phenotypes are regulated to balance host defense and inflammation with
homeostatic functions that resolve inflammation and restore tissue integrity. An associated goal is to
therapeutically modulate macrophages to promote tissue repair while minimizing inflammatory pathology.
 Macrophages assume various phenotypes dependent on ontogeny, tissue-specific factors,
epigenetic programming, and (micro)environmental challenges. Inflammatory macrophages produce
cytokines such as TNF and IL-1 that are important for host defense and inflammation, while reparative and
pro-resolution macrophages produce suppressive and growth factors such as IL-10, VEGF and PDGF
important for tissue repair, wound healing and resolution of inflammation. Recent high dimensional analyses
using flow/mass cytometry and single cell RNA sequencing (scRNAseq) have revealed distinct macrophage
populations and functional phenotypes in different tissues and disease states.
 Wound healing typically progresses through inflammatory, tissue repair, and tissue remodeling
stages. Both inflammatory and repair phases, and a well-regulated balance and transition between them,
are important for effective wound healing. Excessive inflammation, such as occurs in chronic TNF-driven
inflammatory diseases such as rheumatoid arthritis (RA), results in ineffective repair and chronic wounds.
Immune cells including macrophages play important roles in the first two phases of wound healing, and
modulation of macrophage function to improve tissue repair is an emerging therapeutic strategy.
 In the previous project period we investigated mechanisms of crossregulation between the
inflammatory factor TNF and the repair factor IL-4, using primary human macrophages and mouse models
of wound healing. While IL-4 suppressed components of the TNF inflammatory response, the two cytokines
synergized to induce genes associated with resolution of inflammation. The balance between an
inflammatory and reparative macrophage phenotype was regulated in part by SREBP transcription factors.
Myeloid inactivation or pharmacological inhibition of SREBPs accelerated wound healing. scRNAseq
identified novel macrophage populations induced by injury and associated with tissue repair. These data
provide insights into mechanisms that regulate the transition from inflammation to repair, and support our
overarching hypothesis that selective modulation of the immune system can be utilized to improve tissue
repair. In this project we will investigate mechanisms that regulate the balance and transition between
inflammation and tissue repair. We anticipate that our studies will yield insights that can be used to develop
novel therapeutic strategies to enhance wound healing and restore tissue function.

## Key facts

- **NIH application ID:** 10205277
- **Project number:** 2R01AI044938-21A1
- **Recipient organization:** HOSPITAL FOR SPECIAL SURGERY
- **Principal Investigator:** Lionel B Ivashkiv
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $445,000
- **Award type:** 2
- **Project period:** 1999-09-30 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10205277

## Citation

> US National Institutes of Health, RePORTER application 10205277, Inhibition of STAT3 and inflammatory cytokine production (2R01AI044938-21A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10205277. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*