# CREB Programming of Alveolar Macrophage Population and Inflammatory Lung Injury

> **NIH NIH P01** · UNIVERSITY OF ILLINOIS AT CHICAGO · 2024 · $430,548

## Abstract

PROJECT SUMMARY/ABSTRACT
The lung’s ability to recover from severe inflammatory injury depends on its capacity to rapidly mobilize intrinsic
tissue repair pathways. Macrophages (Mɸ), the most abundant sentinel immune cell in lungs, have different
lineages and functions. A key, but poorly understood, aspect of these cells is their intrinsic property to promote
repair after lung injury. In the basal state, the lung contains alveolar Mɸ (AMɸ) (CD11c+/CD11b-/SiglecF+) as
well as a population of interstitial Mɸ (IMɸ) (CD11b+/CX3CR1+/SiglecF-). AMɸ are necessary for restoring lung
homeostasis after lung injury but the mechanisms regulating reparative AMɸ generation remain elusive. It is
clear that a reparative AMɸ population needs to be efficiently and rapidly mobilized, in particular, in the face of
sharp decrease in their number during lung infection and injury. In Project 2, we will address this question based
on the seminal observation that the transcription factor cAMP Response Element Binding (CREB) plays a key
role in giving rise to a reparative AMɸ lineage. In support of this concept, we show that the myeloid-specific
deletion of CREB in mice (Creb∆LyzM mice) resulted in the generation of immature AMɸ
(CD11c+/CD11b+/SiglecFlo), which give rise to inflammatory AMɸ, thus subverting the anti-inflammatory and
reparative function of mature AMɸ. These mice thereby showed clear evidence of lung injury in the basal state
due to the increase in inflammatory AMɸ. Furthermore, lung injury in these mice after LPS was prolonged and
agonal. They showed significantly greater mortality than controls. By studying flow-sorted Mɸ from Creb∆LyzM
lungs, we also found alterations in the expression of regulatory genes such as Pparγ , an essential driver of
reparative AMɸ lineage specification, as well as genes regulating AMɸ metabolism and immune responses.
Further analysis showed that CREB induced the expression of pyruvate dehydrogenase kinase 4 (PDK4). PDK4
in turn suppressed the translocation of pyruvate dehydrogenase complex (PDC) from mitochondria to the
nucleus, thus inhibiting the production of nuclear acetyl-CoA. In the absence of CREB and its target PDK4, PDC
activity was markedly increased which resulted in excessive nuclear acetyl-CoA levels, increased histone
acetylation, and the generation of AMɸ, that were incapable of promoting lung repair. Based on these
observations and with the availability of powerful tools generated by the Cores, in Project 2 we will define the
central role of CREB in generating a pro-resolving AMɸ population through the epigenetic regulation of Pparγ
expression. Our Specific Aims are (Aim 1): to address the role of CREB in mediating the generation of a lung
reparative AMɸ population following lung injury, and (Aim 2): to investigate the role of CREB in signaling the
generation of AMɸ by epigenetically upregulating Pparγ expression. Based on the provocative phenotype of
Creb∆LyzM mice, we believe understanding how reparative AMɸ ...

## Key facts

- **NIH application ID:** 10895348
- **Project number:** 5P01HL151327-04
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT CHICAGO
- **Principal Investigator:** DOLLY MEHTA
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $430,548
- **Award type:** 5
- **Project period:** 2021-09-20 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10895348

## Citation

> US National Institutes of Health, RePORTER application 10895348, CREB Programming of Alveolar Macrophage Population and Inflammatory Lung Injury (5P01HL151327-04). Retrieved via AI Analytics 2026-06-10 from https://api.ai-analytics.org/grant/nih/10895348. Licensed CC0.

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