Capsaicin-induced transcriptomic reprogramming of monocyte-derived macrophages during in vitro differentiation

Introduction. TRPV1 cation channels are known to be activated by cigarette smoke components, particulate matter, and reactive oxygen species, and their expression is increased in alveolar macrophages of patients with chronic obstructive pulmonary disease (COPD).
Aim. To analyze the features of the transcriptome profile of macrophages differentiating from peripheral blood monocytes in vitro under prolonged exposure to the TRPV1 agonist capsaicin.
Materials and methods. Monocytes were isolated from the peripheral blood of five apparently healthy male volunteers (52.2±3.89 years). The cells were differentiated for 10 days in RPMI-1640 medium (10% FCS, 1% penicillin/streptomycin) containing 50 ng/ml GM-CSF or GM-CSF at the same concentration and 50 μM capsaicin. Upon completion of differentiation, total RNA was extracted from the resulting macrophages, mRNA was enriched, and sequencing was performed on the MGISEQ-200 platform in SE50 mode. Data processing included read mapping (Salmon), differential expression analysis (DESeq2), and functional gene enrichment (Cytoscape). In addition, macrophage phenotype was assessed using the MacSpectrum platform.
Results. Macrophage differentiation in the presence of capsaicin was primarily accompanied by signs of activation of protein translation and transport processes, lipid metabolism, and maintenance of replicative potential. At the same time, suppression of biological processes associated with cytokine signaling, response to pathogens, ability to stimulate leukocyte activation and proliferation, as well as cytoskeletal organization and cell motility was observed. Analysis using MacSpectrum revealed a decrease in the polarization index (MPI) and differentiation index (AMDI) in macrophages differentiated in the presence of capsaicin, indicating inhibition of the development of a mature pro-inflammatory phenotype and the emegrence of a hyporesponsive, M0-like state.
Conclusion. Capsaicin, likely mediating its effect primarily through TRPV1, significantly influences macrophage differentiation, leading to the formation of hyporesponsive, incompletely differentiated cells that share several characteristics with alveolar macrophages found in the airways of COPD patients. These data suggest TRPV1-dependent modulation of macrophages as a possible pathogenetic mechanism contributing to this disease.

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