# CREB Instruction of Macrophage Fate and Lung fluid homeostasis

> **NIH NIH R01** · UNIVERSITY OF ILLINOIS AT CHICAGO · 2022 · $159,900

## Abstract

Abstract
Recovery from severe forms of inflammatory vascular injury, such as acute lung injury (ALI), depends on the
lung's capacity to rapidly activate tissue repair pathways. Macrophages (Mφ), the most abundant sentinel
immune cell type in the lung, are required for restoration of tissue-fluid homeostasis following injury, but the
identity of the reparative Mφ subpopulations and how they are generated remain elusive. Here, we have
discovered a subset of the alveolar Mφ (AMφ) population that is required to maintain lung fluid homeostasis
basally and induce tissue repair after injury. Our Supporting Data show that: 1) loss of cAMP Response
Element Binding (CREB) protein expression in myeloid cells (Creb∆LyzM mice) arrest a subpopulation of the AMφ
lineage at the pre-AMφ stage, leading to decreased AMφ generation and increased lung vascular permeability
basally; 2) Creb∆LyzM mice failed to resolve injury post-LPS challenge and died more rapidly after Pseudomonas
aeruginosa infection; 3) transcriptome sequencing (RNAseq) and chromatin accessibility profiling (ATACseq) of
flow-sorted CREB-null AMφ have markedly altered gene expression and chromatin remodeling; and 4) CREB is
required to inhibit excessive production of nuclear acetyl-CoA from the pyruvate dehydrogenase complex (PDC)
through synthesis of pyruvate dehydrogenase kinase 4 (PDK4). Based on these provocative Preliminary Data,
in Aim#1, we will test the hypothesis that CREB transcriptionally promotes differentiation of this barrier
reparative AMφ subpopulation. In Aim#2, we will investigate that CREB regulates reparative AMφ generation
by controlling epigenetic modifications of histones thereby leading to AMφ gene transcription. Here, we will
address the novel concept that the transcriptional activity of CREB is required to upregulate PDK4 expression,
which in turn prevents transport of its target, PDC, from mitochondria to the nucleus thereby suppressing
excessive nuclear acetyl Co-A generation and limiting epigenetic modifications of histones, leading to gene
transcription that induces the barrier reparative AMφ population. These studies will employ a rigorous multi-
omics approach (single-cell RNA-, ATAC-and Chip-sequencing) and functional assays in genetically altered mice
including Rosa-CrebCxcxr3-ERT mice (in which CREB is conditionally deleted in monocytes/interstitial macrophages)
to define the role of CREB transcriptional activity in generating the reparative AMφ population. Understanding
how this barrier reparative AMɸ subset is generated should make it possible to enhance differentiation of this
subset during injury by pharmacological or genetic means, thereby reducing the mortality of ALI and related
conditions.

## Key facts

- **NIH application ID:** 10491210
- **Project number:** 5R01HL155941-02
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT CHICAGO
- **Principal Investigator:** DOLLY MEHTA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $159,900
- **Award type:** 5
- **Project period:** 2021-09-20 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10491210

## Citation

> US National Institutes of Health, RePORTER application 10491210, CREB Instruction of Macrophage Fate and Lung fluid homeostasis (5R01HL155941-02). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10491210. Licensed CC0.

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