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Unveiling the Mechanistic Role of Macrophages and Therapeutic Targeting in Lung Fibrosis

Award Number: R01HL183230
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/24/2026
PERIOD OF PERFORMANCE END DATE: 05/31/2030

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Unveiling the Mechanistic Role of Macrophages and Therapeutic Targeting in Lung Fibrosis - ABSTRACT Idiopathic pulmonary fibrosis (IPF) is the most common and pernicious form of lung fibrosis, which is characterized by progressive alveolar destruction, failed regeneration and unrelenting fibrogenesis. Lung macrophages have long been recognized to play a critical role in the pathogenesis of this disease. Recent evidence further demonstrated that monocyte derived alveolar macrophages (Mo-AMs), but not tissue resident alveolar macrophages (TR-AMs), were responsible for the pro-fibrotic activity of this type of cells. Despite these inspiring progresses, knowledge gaps remain in the understanding of how the Mo-AM phenotype and cell fate are regulated during the course of fibrogenesis, how modulation of a potential regulatory mechanism in the Mo- AMs may affect the progression of this pathology, and how to target the regulatory mechanism in the Mo-AMs to treat lung fibrosis. In our preliminary studies, we found that there was a markedly elevated expression of TREM2, a receptor currently under intense investigations for its role in regulating microglial phenotype in Alzheimer's disease, on Mo-AMs compared to TR-AMs from fibrotic mouse lungs, as well as on IPF AMs compared to normal control AMs. We also found enriched sphingomyelin (SM) and phosphatidylcholine (PC), two classes of high-avidity TREM2 ligands, in the alveolar space that Mo-AMs will encounter in mice with bleomycin induced lung fibrosis. We found that SM activated TREM2 and promoted TREM2 dependent macrophage survival and pro-fibrotic expression in vitro, and the SM activities were abolished by soluble TREM2 (sTREM2) and TREM2 blocking antibody. In mice, ablation of TREM2 protected the animals from bleomycin induced lung fibrosis. TREM2-/- Mo-AMs demonstrated increased apoptosis and diminished expression of pro- fibrotic mediators. Furthermore, consistent with their TREM2 receptor blocking activities in vitro, sTREM2 and the TREM2 blocking antibody ameliorated bleomycin induced lung fibrosis. Our data suggest that Mo-AM TREM2 critically contributes to the pathogenic role of this subset of macrophages in pulmonary fibrosis. Targeting Mo-AM TREM2 may therefore represent a novel strategy to treat lung fibrosis through curbing these exuberantly pro-fibrotic cells. We will test our hypothesis in three specific aims: Aim 1. Define how TREM2 regulates the profibrotic phenotype and cell fate of Mo-AMs in vitro and in vivo. Aim 2. Evaluate the therapeutic efficacy of TREM2 modulation in experimental lung fibrosis. Aim 3. Determine how TREM2 controls the profibrotic phenotype and survival of IPF alveolar macrophages in vitro and in precision-cut lung slices (PCLS). The completion of these studies will substantially improve our understanding of the regulatory mechanism underlying the critical contribution of Mo-AMs, the dominantly pathogenic macrophage subset, to the progression of lung fibrosis. This study will also establish proof of concept for targeting TREM2 as lung fibrosis therapeutics, paving the road for developing a specific TREM2 blocking antibody into a treatment of this pathology.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $740,400 )
2026	2026	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Lung Diseases Research	000	1	8/27/2026	NEW	$740,400
														Subtotal = $740,400

Grand Total All Awards = $740,400

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Unveiling the Mechanistic Role of Macrophages and Therapeutic Targeting in Lung Fibrosis

Award Number: R01HL183230

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 08/24/2026

PERIOD OF PERFORMANCE END DATE: 05/31/2030

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