The Janus Kinase inhibitor tofacitinib impacts human dendritic cell differentiation and favours M1 macrophage development

Article Article scientifique Article The Janus Kinase inhibitor tofacitinib impacts human dendritic cell differentiation and favours M1 macrophage development eng 2020 author Stalder Monney Romaine 22084 author Zhang Bin 883154 author Wrobel Ludovic 671544 author Boehncke Wolf-Henning 779122 author Brembilla Nicolo 703016 71-78 10.1111/exd.14059 31721311 0906-6705 https://onlinelibrary.wiley.com/doi/full/10.1111/exd.14059 Several cytokines signalling via Janus Kinase (JAK) proteins have been implicated in the pathogenesis of immune-mediated inflammatory diseases, including psoriasis and rheumatoid arthritis (RA). Tofacitinib, a small JAK inhibitor, is approved for the treatment of RA and has demonstrated good efficacy in psoriasis phase III clinical trials. In this work, we analysed the in vitro effects of tofacitinib on the functions of human dendritic cells (DCs) and macrophages. When assessing the effects of tofacitinib on monocyte-derived DCs, we observed reduced differentiation of monocytes into immature DCs, as evidenced by a decreased transcription of CD209 and CD80. Phenotype assessment in the presence of tofacitinib suggested a switch towards a M1-like macrophage phenotype, as evidenced by the expression of M1 markers such as iNOS, as well as cytokines typically expressed by M1 cells, including IL-12 and IL-23. Of note, Arginase1 and CD200R, typically expressed by M2 cells, were absent on tofacitinib-treated DCs. Furthermore, tofacitinib affected the response of differentiated DCs to maturation stimuli such as LPS and IFNγ, resulting in a partial up-regulation of IL-23 and down-regulation of IL-12, as assessed by qPCR. When investigating macrophage development, we found that tofacitinib inhibited the ability of monocytes to differentiate and polarize into regulatory M2 macrophages, while rather enhancing the ability to develop into inflammatory M1-like macrophages, as evidenced by decreased expression of the M2 marker CD200R and enhanced production of IL-12 and IL-23. In conclusion, tofacitinib impacts the differentiation of human DCs and macrophages, it particularly favours generation of M1-like pro-inflammatory macrophages. Dendritic cells IL-23 Janus kinase inhibitor Macrophages Tofacitinib Dewey 616 Dewey 616.07 137 Département de pathologie et immunologie 21F 56 Département de médecine 221 false 576 Inflammation cutanée 919 Experimental Dermatology 29 1 2a2255ed-5dfa-4131-aecb-85c78d098267 Article (Published version) Restricted 31721311.pdf 1101779 application/pdf restrictedAccess Faculté de médecine / Section de médecine fondamentale / Département de pathologie et immunologie Faculté de médecine / Section de médecine clinique / Département de médecine

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The Janus Kinase inhibitor tofacitinib impacts human dendritic cell differentiation and favours M1 macrophage development	Experimental Dermatology			2020	384	0

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Zhang, Bin