# Macrophage nuclear receptors, metabolism and immune effectors during health and M. tuberculosis infection

> **NIH NIH R01** · TEXAS BIOMEDICAL RESEARCH INSTITUTE · 2021 · $706,804

## Abstract

Project Summary/Abstract
Human lungs, while mediating air exchange in the alveoli, are constantly exposed to pollutants, allergens, and
microbes. Resident alveolar macrophages (AMs) must clear insults without damaging the alveoli. Thus, AMs
possess a unique, highly regulated immune response that results in inefficient clearance of some airborne
microbes, especially host-adapted pathogens like Mycobacterium tuberculosis (M.tb), the causative agent of
tuberculosis (TB), a top 10 cause of death worldwide. AM development, maintenance and biology are poorly
understood, especially for human macrophages and in regards to the effect of the local environment, e.g.
surfactant, which lines the alveoli, and locally produced cytokines such as TGFβ. Failure to completely
understand the molecular events underlying AM development and biology creates a critical barrier to
developing new treatment strategies that target the lung. The long-term objective of this ongoing research
program is to identify signaling pathways associated with transcriptional regulators and inflammatory
metabolites that dictate AM biology and how these are co-opted by the host-adapted intracellular pathogen
M.tb, to enhance its growth. New data in the laboratory indicate that M.tb, surfactant proteins and TGFβ
regulate expression of the nuclear receptors (NRs) peroxisome proliferator-activated receptor gamma
(PPARγ), Rev-erbα, Nur77, and Nurr1. NRs are a large family of structurally conserved, ligand activated
transcription factors, which enable macrophages to sense their local environment and shape immune
responses. In this regard, NRs sit at the interface of metabolism (particularly lipid and eicosanoid) and
immunity, and are increasingly recognized as relevant to M.tb pathogenesis, yet are unexplored in the context
of the lung and M.tb. It is critical to understand if/how NRs cooperate to regulate AM biology in ways that
impact responses to M.tb. Expression and function of NRs are tightly regulated to provide a balanced immune
response. The hypothesis for this proposal is that NRs modify eicosanoid metabolism and protective immune
responses, thereby making AMs more susceptible to M.tb and that M.tb augments select endogenous
pathways to further dampen the AM immune response to enhance its survival. The Specific Aims are to: 1)
determine the effect of surfactant and local cytokines on human macrophage NR expression and activity and
how this is modulated by M.tb, 2) characterize newly discovered PPARγ effectors and their regulation of lipid
metabolism during M.tb infection, and 3) determine whether PPARγ, Rev-erbα, Nur77 and Nurr1, as well as
PPARγ effectors, are viable host-directed therapeutic targets for TB. Human AMs and the tractable model of
human blood monocyte-derived macrophages (MDMs), biochemical and genetic techniques, and mouse
models will be used to study the role of NRs, and their effectors, in TB. Since NRs regulate metabolism and
inflammation in a tissue, gene and signal-...

## Key facts

- **NIH application ID:** 10215474
- **Project number:** 5R01AI136831-03
- **Recipient organization:** TEXAS BIOMEDICAL RESEARCH INSTITUTE
- **Principal Investigator:** Larry S. Schlesinger
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $706,804
- **Award type:** 5
- **Project period:** 2019-08-07 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10215474

## Citation

> US National Institutes of Health, RePORTER application 10215474, Macrophage nuclear receptors, metabolism and immune effectors during health and M. tuberculosis infection (5R01AI136831-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10215474. Licensed CC0.

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