Construct validation of machine learning models for predicting surgical site infection risk following ankle fracture surgery.

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Abstract

[Indexed for MEDLINE] 6. J Biol Chem. 2018 Feb 23;293(8):3003-3012. doi: 10.1074/jbc.M117.809780. Epub 2017 Dec 26. MicroRNA-146 and cell trauma down-regulate expression of the psoriasis-associated atypical chemokine receptor ACKR2. Shams K(1), Kurowska-Stolarska M(2), Schütte F(3), Burden AD(4), McKimmie CS(5), Graham GJ(6). Author information: (1)Skin Research Group, Leeds Institute of Rheumatic and Musculoskeletal Medicine, National Institute for Health Research Biomedical Research Centre; Department of Dermatology, Chapel Allerton Hospital, Leeds LS7 4SA, United Kingdom; Chemokine Research Group. (2)Institute of Infection, Immunity and Inflammation, 120 University Place, University of Glasgow, Glasgow G12 8TA, Scotland, United Kingdom. (3)Chemokine Research Group. (4)Institute of Infection, Immunity and Inflammation, 120 University Place, University of Glasgow, Glasgow G12 8TA, Scotland, United Kingdom; Department of Dermatology, Lauriston Building, Edinburgh EH3 9HA, Scotland, United Kingdom. (5)Chemokine Research Group; Virus Host Interaction Team, Leeds Institute of Cancer and Pathology, University of Leeds, St. James' University Hospital, Leeds LS9 7TF, United Kingdom. (6)Chemokine Research Group. Electronic address: gerard.graham@glasgow.ac.uk. Chemokines are the principal regulators of leukocyte migration and are essential for initiation and maintenance of inflammation. Atypical chemokine receptor 2 (ACKR2) binds and scavenges proinflammatory CC-chemokines, regulates cutaneous T-cell positioning, and limits the spread of inflammation in vivo Altered ACKR2 function has been implicated in several inflammatory disorders, including psoriasis, a common and debilitating T-cell-driven disorder characterized by thick erythematous skin plaques. ACKR2 expression is abnormal in psoriatic skin, with decreased expression correlating with recruitment of T-cells into the epidermis and increased inflammation. However, the molecular mechanisms that govern ACKR2 expression are not known. Here, we identified specific psoriasis-associated microRNAs (miRs) that bind ACKR2, inhibit its expression, and are active in primary cultures of human cutaneous cells. Using both in silico and in vitro approaches, we show that miR-146b and miR-10b directly bind the ACKR2 3'-UTR and reduce expression of ACKR2 transcripts and protein in keratinocytes and lymphatic endothelial cells, respectively. Moreover, we demonstrate that ACKR2 expression is further down-regulated upon cell trauma, an important trigger for the development of new plaques in many psoriasis patients (the Koebner phenomenon). We found that tensile cell stress leads to rapid ACKR2 down-regulation and concurrent miR-146b up-regulation. Together, we provide, for the first time, evidence for epigenetic regulation of an atypical chemokine receptor. We propose a mechanism by which cell trauma and miRs coordinately exacerbate inflammation via down-regulation of ACKR2 expression and provide a putative mechanistic explanation for the Koebner phenomenon in psoriasis. © 2018 by The American Society for Biochemistry and Molecular Biology, Inc. DOI: 10.1074/jbc.M117.809780 PMCID: PMC5827444