# Modulation of Macrophage Polarization by Heterotrimeric G proteins: Implications of Gastrointestinal Inflammation

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2020 · $485,810

## Abstract

Abstract:
Chronic inflammatory disorders, whether it is arthritis, atherosclerosis, type II diabetes, or inflammatory bowel
disease (IBD) are diseases that severely debilitate millions of people worldwide. Immune deregulation, microbial
dysbiosis, genetics, and environmental factors, all contribute to the chronic inflammation that drives the disease.
More specifically, chronic inflammatory disorders are fueled by increased expression of inflammatory cytokines
and the recruitment of immune cells, including dysfunctional proinflammatory macrophages, that recruit, incite
and propagate pro-inflammatory T-cell responses. In order to develop novel immunologic therapies, a deeper
understanding of the mechanisms of immune homeostasis is needed, including those that address macrophage
dysfunction, which plays an integral role in perpetuating inflammation. Because the molecular mechanisms that
govern chronic inflammatory responses in macrophages are yet to be fully elucidated or exploited as therapeutic
targets, this is a need that is both urgent and unmet. Using bioinformatics (sequence homology) we first identified
GIV (a.k.a Girdin), a guanine-nucleotide exchange modulator (GEM) for trimeric G protein, Gαi, as a novel
binding partner of TLR4. Subsequent work not just validated and characterized this interaction in-depth, but also
revealed that GIV is a regulator of TLR4 signaling and a key determinant of macrophage polarization and
inflammatory cytokine expression. GIV expression is suppressed in M1 and upregulated in M2-polarized primary
macrophages, and GIV-GEM-dependent G protein signaling is required for the suppression of pro- and
upregulation of anti-inflammatory cytokines in response to the ligand for TLR4, lipopolysachharide (LPS). It is
hypothesized that the GIV→Gαi cascade reduces inflammation and favors healing by switching macrophages
from the pro-inflammatory M1 to the anti-inflammatory M2 polarized state. This proposal seeks to elucidate how
GIV-GEM regulates such a "switch" and reveal the consequences of deregulated GIV→Gαi signaling axis in the
gut where macrophages within the largest immune system face-off the largest reservoir of LPS (i.e., luminal
microbes). Our aims are: 1) Dissect GIV's role in shaping the dynamics of TLR4 signalosome during
inflammation using a combination of in vitro protein-protein interaction assays, 3D-homology model-guided
mutagenesis, immunoprecipitation assays, immunofluorescence microscopy, and specific single-AA mutants; 2)
Determine GIV's ability to modulate macrophage inflammatory programs using RNA-seq transcriptome
analysis, cell-based macrophage polarization assays, and assays evaluating bacterial uptake and clearance;
and 3) Investigate the consequences of GIV dysregulation in intestinal inflammation using mouse models
of inflammation e.g., LPS challenge; DSS-induced chemical colitis and infectious colitis (Salmonella and
Citrobacter), with or without pharmacologic modulators of GIV-GEM signaling. In...

## Key facts

- **NIH application ID:** 9932323
- **Project number:** 5R01AI141630-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Pradipta Ghosh
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $485,810
- **Award type:** 5
- **Project period:** 2019-05-21 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9932323

## Citation

> US National Institutes of Health, RePORTER application 9932323, Modulation of Macrophage Polarization by Heterotrimeric G proteins: Implications of Gastrointestinal Inflammation (5R01AI141630-02). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/9932323. Licensed CC0.

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