# S1PR1 Mislocalization in Lung Endothelium Regulates Innate Immune Function and Mediates Inflammatory Lung Injury

> **NIH NIH P01** · UNIVERSITY OF ILLINOIS AT CHICAGO · 2023 · $428,549

## Abstract

ABSTRACT
Uncontrolled accumulation of inflammatory cells in the airspace paired with vascular injury causes lethal acute
lung injury (ALI). The microvascular endothelium, with which immune cells are continuously in contact with, plays
a critical role in maintaining lung homeostasis basally and after infection. Sphingosine-1-phosphate receptor-1
(S1PR1), a G-protein coupled receptor (GPCR) expressed on the endothelial cell (EC) surface, is a well-known
mediator of “barrier protection” and “resolution of inflammation”. Here we have discovered that S1PR1 can also
trigger counterproductive signaling, thus changing the lung vascular niche. The focus of Project 1 is to identify
post-translationally modified S1PR1 as a significant molecular switch that epigenetically modifies EC from an
anti-inflammatory phenotype to an immune-active phenotype, leading to irreversible inflammatory lung injury.
Our Supporting Data show that: 1) inflammatory cytokines (e.g., TNFα) produced during inflammatory injury
phosphorylates S1PR1 on tyrosine143 (Y143-S1PR1); 2) Y143-phosphorylated S1PR1 in turn signaled receptor
translocation and localization to the endoplasmic reticulum (ER), 3) the chaperone protein BiP (Binding
immunoglobulin Protein) was essential for the translocation and binding of Y143-S1PR1 to the ER membrane, 4)
the ER-associated Y143-S1PR1 subsequently bound to the intracellular heteromeric GTP binding protein Gi, and
when activated by intracellular S1P augmented store-operated calcium entry (SOCE) in a Gi-dependent manner,
and 5) rendering S1PR1 constitutively phosphorylated (by editing Y143 to D143) in EC of mice increased lung
inflammatory injury. Lung EC also gained epigenetic modifications of genes inducing vascular development and
myeloid cells differentiation and activation following injury by Pseudomonas aeruginosa, suggesting injury-
specific modulation of EC epigenome. Based on these provocative data, Project 1 will test the hypothesis that
ER-resident Y143-S1PR1 is a crucial point of confluence for key signaling events with the potential to rewire the
EC epigenome, shifting EC into an inflammatory phenotype leading to intractable lung injury. Our Specific Aims
are: Aim #1: to address the role of Y143 phosphorylation of S1PR1 in the ER positioning of S1PR1 and
reprogramming of lung endothelium, and thereby leading to inflammatory lung injury; and Aim #2: to study the
role of chaperone protein BiP interaction with Y143 phosphorylated-S1PR1 in stabilizing S1PR1 at ER membrane
and mediating the shift to inflammatory phenotype in lung EC. We will use genetically modified mice generated
using Crisper-Cas9 gene editing as well as EC-specific S1PR1 null mice and tools available in Cores such as
epigenetic analysis (Core B), multichannel cellular imaging (Core C), and 2-photon imaging of lung EC and
immune cells in living mouse (Core C) to define mechanistically how ER-resident Y143-S1PR1 in EC centralizes
these signaling events to control the fate of i...

## Key facts

- **NIH application ID:** 10706510
- **Project number:** 5P01HL160469-02
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT CHICAGO
- **Principal Investigator:** DOLLY MEHTA
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $428,549
- **Award type:** 5
- **Project period:** 2022-09-20 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10706510

## Citation

> US National Institutes of Health, RePORTER application 10706510, S1PR1 Mislocalization in Lung Endothelium Regulates Innate Immune Function and Mediates Inflammatory Lung Injury (5P01HL160469-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10706510. Licensed CC0.

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