931 Distinct regulatory transcriptional profiles reveal a wound healing phenotype for inflammatory macrophages exposed to TNF-Adalimumab complexes in vitro

Abstract

Adalimumab (ADA) is the only FDA-approved treatment for moderate to severe hidradenitis suppurativa (HS), a chronic inflammatory disease characterized by recurrent abscesses/nodules and draining wounds. However, the pathogenic role of TNFα and the mechanism of action (MOA) of adalimumab in HS wound healing remain unknown. We have previously demonstrated that TNF-adalimumab complexes show stronger inhibitory effect on inflammatory macrophage (M1 Mφ) development by diverting these cells towards a wound healing (M2) Mφ phenotype in comparison with TNF-etanercept (ETN) or TNF-certolizumab pegol (CZP) complexes. In this study, we sought to refine the molecular signatures associated with TNF-ADA-treated M1 Mφ to advance our understanding of the MOA of ADA in improving wound healing in HS. Transcriptome analyses were carried out for LPS + IFN-γ induced M1 Mφ in the presence or absence of TNF ± anti-TNF agents (ADA, ETN or CZP) as preformed complexes by next-generation RNA sequencing. Differential expression analysis showed 184 differentially expressed genes that were specific to TNF-ADA-treated M1 Mφ compared with those from TNF-ETN- or TNF-CZP-treated M1 Mφ. Ingenuity pathway analysis revealed unique regulatory profiles for TNF-ADA-treated M1 Mφ, which were not observed for those treated with either TNF-ETN or TNF-CZP, including inhibition of matrix metalloproteases and promotion of IL-10 signaling, HIF1a signaling and Fcγ receptor-mediated phagocytosis in macrophages. Each of these pathways has been shown to contribute to the process of wound healing. In conclusion, our in-vitro findings demonstrate that a distinct wound healing profile may be present in TNF-ADA-treated M1 Mφ, suggesting a possible MOA of ADA in HS wound healing. Additional in vitro and in vivo wound healing studies need to be done to validate the effects of TNF-ADA in this process.