FFAR2 and FFAR3 Modulate Cigarette Smoke-induced Emphysema through Distinct Inflammatory Pathways 2307232

Abstract Introduction Despite the lack of effective treatments for chronic obstructive pulmonary disease (COPD), increasing evidence from studies on the gut—lung axis demonstrates the role of short-chain fatty acids (SCFAs) in respiratory immune regulation. SCFAs exert anti-inflammatory effects in the lung by activating GPCRs (FFAR2 and FFAR3) and inhibiting histone deacetylase2 (HDAC2). However, the predominant mechanism responsible for COPD alleviation remains unclear. This study aims to evaluate the differential roles of FFAR2 and FFAR3 activation in modulating COPD progression. Methods Mice were exposed to cigarette smoke (CS) for emphysema model with/without propionate, 4-CMTB (selective FFAR2 agonist), or AR420626 (selective FFAR3 agonist). Results CS induced airspace enlargement and mechanical dysfunction, which were improved by agonist treatment. AR420626-treated group restored airway resistance and compliance, accompanied by broad suppression of inflammatory and remodeling genes by qPCR. In contrast, 4-CMTB-treated group improved tissue elastance and reduced neutrophil and monocyte infiltration in bronchoalveolar lavage fluid. Cytokine profiling showed receptor-specific modulation: FFAR3 activation decreased TNF-α and IL-18 while increasing IL-10, whereas FFAR2 reduced IL-6 and IL-17A. Proteomics showed suppression of Th17-associated proteins, with FFAR3 reducing IL-9/IL-17F and FFAR2 reducing IL-9/CXCL12. Flow cytometry showed that FFAR2 activation reduced Th1/Th17 populations and increased M2 macrophage polarization. Western blot and TUNEL assay confirmed that FFAR3 inhibited NLRP3-caspase signaling and alveolar apoptosis, whereas FFAR2 attenuated MAPK/NF-kB inflammatory pathways. Conclusion Selective activation of FFAR3 restored alveolar architecture and suppressed apoptotic signaling, whereas FFAR2 attenuated inflammatory cytokine production and immune cell infiltration. These findings reveal distinct receptor-specific SCFA pathways and highlight FFAR2 and FFAR3 as distinct therapeutic targets in COPD. Funding Source This study was supported by NRF grant (RS-2023-NR077159, RS-2023-00222687, RS-2022-NR067421) and NIH grant (No.2024ER080601) funded by Korean government. Topic Categories Immune Response Regulation: Molecular Mechanisms (IRM)