Mohr Annika, Besser Manuela, Broichhausen Sonja, Winter Maximiliane, Bungert Alexander D, Strücker Benjamin, Juratli Mazen A, Pascher Andreas, Becker Felix
Department of General, Visceral and Transplant Surgery, University Hospital Münster, 48149 Münster, Germany.
J Clin Med. 2023 May 9;12(10):3359. doi: 10.3390/jcm12103359.
There is compelling evidence suggesting a pivotal role played by macrophages in orchestrating intestinal wound healing. Since macrophages display significant plasticity and heterogeneity, exhibiting an either classically activated (M1-like) or alternatively activated (M2-like) phenotype, they can aggravate or attenuate intestinal wound healing. Growing evidence also demonstrates a causal link between impaired mucosal healing in inflammatory bowel disease (IBD) and defects in the polarization of pro-resolving macrophages. By targeting the switch from M1 to M2 macrophages, the phosphodiesterase-4 inhibitor Apremilast has gained recent attention as a potential IBD drug. However, there is a gap in our current knowledge regarding the impact of Apremilast-induced macrophages' polarization on intestinal wound healing. The THP-1 cells were differentiated and polarized into M1 and M2 macrophages, and subsequently treated with Apremilast. Gene expression analysis was performed to characterize macrophage M1 and M2 phenotypes, and to identify possible target genes of Apremilast and the involved pathways. Next, intestinal fibroblast (CCD-18) and epithelial (CaCo-2) cell lines were scratch-wounded and exposed to a conditioned medium of Apremilast-treated macrophages. Apremilast had a clear effect on macrophage polarization, inducing an M1 to M2 phenotype switch, which was associated with NF-κB signaling. In addition, the wound-healing assays revealed an indirect influence of Apremilast on fibroblast migration. Our results support the hypothesis of Apremilast acting through the NF-κB-pathway and provide new insights into the interaction with fibroblast during intestinal wound healing.
有令人信服的证据表明巨噬细胞在协调肠道伤口愈合中起关键作用。由于巨噬细胞表现出显著的可塑性和异质性，呈现出经典激活（M1样）或替代激活（M2样）表型，它们可以加重或减轻肠道伤口愈合。越来越多的证据还表明，炎症性肠病（IBD）中黏膜愈合受损与促解决巨噬细胞极化缺陷之间存在因果关系。通过靶向从M1巨噬细胞向M2巨噬细胞的转变，磷酸二酯酶-4抑制剂阿普司特最近作为一种潜在的IBD药物受到关注。然而，我们目前对于阿普司特诱导的巨噬细胞极化对肠道伤口愈合的影响的认识存在空白。将THP-1细胞分化并极化为M1和M2巨噬细胞，随后用阿普司特处理。进行基因表达分析以表征巨噬细胞的M1和M2表型，并确定阿普司特可能的靶基因和相关途径。接下来，对肠道成纤维细胞（CCD-18）和上皮细胞（CaCo-2）系进行划痕损伤，并使其暴露于经阿普司特处理的巨噬细胞的条件培养基中。阿普司特对巨噬细胞极化有明显影响，诱导M1向M2表型转换，这与NF-κB信号传导有关。此外，伤口愈合试验揭示了阿普司特对成纤维细胞迁移的间接影响。我们的结果支持阿普司特通过NF-κB途径发挥作用的假说，并为肠道伤口愈合过程中与成纤维细胞的相互作用提供了新的见解。
