# Novel anti-inflammatory mesothelial signaling to the spleen

> **NIH NIH R21** · AUGUSTA UNIVERSITY · 2020 · $191,719

## Abstract

Project Summary/Abstract
Sepsis is a complex lethal condition defined as “life- threatening organ dysfunction caused by a dysregulated
host response to infection”. In the U.S, sepsis is related to ~1 million hospitalizations annually, and the incidence
of sepsis continues to rise. The mortality rate from in patients with sepsis remains unacceptably high. Novel data
from our laboratory recently demonstrated that simply moving the spleen to midline and then returning it to its
original position causes development of splenic capsular fibrosis and a pro-inflammatory shift in the immune cell
phenotype of the spleen. While similar findings have been reported in mice, it remains unclear how these
maneuvers promote a pro-inflammatory phenotype. Our novel data indicate that specialized mesothelial cells
that form connections to the splenic capsule may transmit tonic anti-inflammatory signals to spleen via
cholinergic signaling through alpha 7 nicotinic receptors. In addition to markers of cholinergic signaling, these
mesothelial cells strongly express neuronal markers and display neuronal-like organelles within their cytoplasm.
As the connections themselves are made of collagen lined with mesothelial cells, splenic capsular fibrosis
following disruption of these connections may represent a physiological response to try to re-establish
mesothelial cell to cell signaling. The primary goal of this proposal is to determine whether cholinergic signaling
through specialized mesothelial cells does indeed transmit tonic anti-inflammatory signals to the splenic capsule
and whether disruption of this signaling has a functional response, exacerbating the systemic inflammatory
response to endotoxin. As such, Aim 1 will test whether `Surgical disruption of mesothelial signaling to the splenic
capsule results in a prolonged anti-inflammatory profile and exacerbated inflammatory response to endotoxin'.
We will access the spleen in rats via a flank incision and clear the spleen of mesothelial connections without
interfering with the spleen. Baseline immune profiles (flow cytometry/cytokine analysis) and the physiological
response to experimental inflammatory shock (endotoxin) in anesthetized disrupted and sham surgical rats will
be determined 24 hours, 21 days and 3 months following surgical disruption of mesothelial connections to the
spleen Aim 2 will test whether `Non-neuronal cholinergic signaling between mesothelial cells mediates a tonic
anti-inflammatory response in the spleen'. Global deletion of α7nAChR in mice results in a pro-inflammatory
splenic phenotype however, the cell type(s) mediating this effect remain unclear. We will use Wilms tumor 1
homolog gene promoter Cre and Chrna7tm1 floxed mice to `knockout' α7nAChR specifically in mesothelial cells.
We predict that loss of the α7nAChR specifically in mesothelial cells will promote a pro-inflammatory phenotype
in the spleen. If our hypothesis is correct, neuronal like signaling between distal sites through me...

## Key facts

- **NIH application ID:** 9941728
- **Project number:** 1R21AI150723-01
- **Recipient organization:** AUGUSTA UNIVERSITY
- **Principal Investigator:** Paul Michael O'Connor
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $191,719
- **Award type:** 1
- **Project period:** 2020-02-01 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9941728

## Citation

> US National Institutes of Health, RePORTER application 9941728, Novel anti-inflammatory mesothelial signaling to the spleen (1R21AI150723-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9941728. Licensed CC0.

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