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Fatty Acid Binding Protein 5-deficiency impairs alveolar macrophage function and metabolism

ABSTRACT: Rationale: Macrophages are large mononuclear immune cells that participate in host protection, not only by phagocytosing foreign or infected cells and initiating inflammatory responses, but also by contributing to the resolution of inflammation. Chronic Obstructive Pulmonary Disease (COPD) is characterized by increased numbers of macrophages in lung tissue, with altered engulfment capabilities. However, the molecular pathways leading to macrophage dysfunction in COPD remain unclear. Using integrated genetics and genomics approaches, we previously identified Fatty Acid Binding Protein 5 (FABP5) as a key target in the resolution of airway inflammation that exhibits decreased expression in COPD patients. Objective: To define the significance of macrophage FABP5 by comparing the resolution of inflammation in WT and FABP5-/- mice following nontypeable Haemophilus influenzae (NTHi) infection or LPS sterile inflammation. Methods: Immune and metabolic responses were analyzed using functional assays, flow cytometry, ELISA, cell metabolic profiling and tracing, as well as ATAC-seq. Results: FABP5-/- mice exhibited impaired efferocytosis, reflected by a reduction of apoptotic cell engulfment by alveolar macrophages. This was accompanied by a reduction in fatty acid uptake and fatty acid -oxidation, a reduction in mitochondrial respiration, an accumulation of TCA cycle and glycolysis metabolites, and an increased chromatin accessibility for AP-1 family members. Conclusions: FABP5-deficient alveolar macrophages failed to initiate reparative metabolic programming, which is critical for the resolution of inflammation. Our data suggest that increasing FABP5 expression could provide a metabolic switch that facilitates macrophage conversion to a pro-resolving phenotype and restores macrophage efferocytic functions in the lungs of COPD patients.

ORGANISM(S): Mus musculus

PROVIDER: GSE332772 | GEO | 2026/05/28

REPOSITORIES: GEO

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Project description:Differential susceptibility to recurrent infection and exacerbation in COPD is not well understood. Here we investigated the potential impact of genetic variation in Fatty Acid Binding Protein 5 (FABP5), a metabolic regulator we previously demonstrated to be downregulated in COPD and further downregulated in patients reporting one or more exacerbation. Through negative binomial analysis of the COPDGene SNP dataset, we identified 5 novel linked single nucleotide polymorphisms (SNPs) across the FABP5 locus that were significantly associated with severe exacerbations in a Non-Hispanic White cohort (rs4338057, rs12549270, rs202275, rs202277, and rs202279). We integrated multiple sources of previously published data to prioritize SNPs most likely to exert regulatory function. Ultimately, rs202275 emerged as the lead candidate due to unique alignment with the loading site of a bidirectional RNA Pol II signature of active enhancer utilization in our recently published patient-derived airway epithelial PRO-seq dataset, suggesting a critical regulatory role for the region harboring this variant. Using Micro-C genome-wide chromosome conformation capture, we found that the region harboring rs202275 makes three-dimensional physical contacts with the FABP5 transcription start site (TSS), suggesting the SNP region could regulate FABP5 transcription through a looping mechanism. To examine SNP function, we analyzed previously deposited gene-array data (GEO Accession #GSE42057) from peripheral blood mononuclear cell (PBMC) samples and found that COPD patients carrying the rs202275 risk allele (T) express significantly lower levels of FABP5 compared to non-carrier patients. Seahorse real-time mitochondrial respiration assays in freshly isolated PBMCs further revealed disrupted oxidative phosphorylation in cells from patients carrying the rs202275 risk allele. As macrophage polarization from pro-inflammatory toward pro-resolving phenotype is dependent on oxidative metabolism, the functional impact of the rs202275 risk allele and associated reduction in FABP5 transcription may contribute to increased or prolonged systemic inflammation, thereby increasing susceptibility to exacerbation in COPD.

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Fatty Acid Binding Protein 5-deficiency impairs alveolar macrophage function and metabolism

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