MicroRNA-146 and cell trauma down-regulate expression of the psoriasis-associated atypical chemokine receptor ACKR2

Abstract

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.

Koebner phenomenon leading to the formation of new psoriatic lesions: evidences and mechanisms

“…Along with it, the presence of α 2 β1 integrin in the suprabasal epidermal layers (normally it is in basal epidermal layer) [98,99]; increased expression of S100A7 (psoriasin) and S100A15 (koebnerisin) in the epidermis [26]; predominance of CD4 + cells over the CD8 + T cells in the epidermis [5]; increase in chemokines viz. CXCL8 and CCL20 [30], down-regulation of mechanosensitive polycystin 1 protein [27], ACKR2 [28], and ionotropic NMDARs on the keratinocytes [114] also contribute in the development of secondary psoriatic lesions following skin injury.…”

“…Using in silico and in vitro studies, it was shown that miR-146b directly binds to the 3 -UTR region of ACKR2 gene, leading to decreased expression of ACKR2 in keratinocytes. Accordingly, it may be suggested that the changes in the epigenetic regulation (via miR-146b) of an atypical chemokine receptor with the down-regulation of the expression of latter protein may be responsible for the inappropriate and excessive immune response during the Koebner phenomenon in psoriasis [28].…”

“…Indeed, a number of agents/triggers have been reported to induce the development of new psoriatic lesions in healthy skin areas and these include, tattooing skin, radiations, skin incision, viral infections, and striae etc [17][18][19]. The different mechanisms that may possibly contribute in inducing the development of new psoriatic lesions as Koebernization include the involvement of mast cell-derived inflammatory mediators [20][21][22], nerve growth factor (NGF) and its receptor system [23], vascular endothelial growth factor (VEGF) [24], α 2 β1 integrins [25], S100A7 (psoriasin) and S100A15 (koebnerisin) [26], increase in the ratio of CD4 + /CD8 + T cells [5], down-regulation of polycystins [27], down-regulation of atypical chemokine receptor 2 (ACKR2) [28], decreased expression of N-methyl-d-aspartate (NMDA) receptor (NMDAR) on the keratinocytes [29] and increase in chemokines [30]. The present review discusses the role of Koebner phenomenon in the development of new psoriatic lesions at the healthy body parts in response to an injury with possible mechanisms.…”

Hand‐foot‐and‐mouth‐disease‐induced Koebner phenomenon in psoriasis

“…Recent novel studies have proposed a molecular mechanism for KP in psoriasis [ 8,9 ] . Researchers demonstrated that cell trauma downregulates the expression of the atypical chemokine receptor 2 (ACKR2), a "chemokine scavenger" that limits infl ammation in psoriasis, potentially via upregulation of microRNA-146b [ 9 ] . Thus, the physical trauma in HFMD lesions could be the fi nal trigger that leads to psoriatic plaque development in an infl ammatory setting.…”

Understanding psoriasis: Role of miRNAs (Review)

“…According to Pivarsci et al , due to Toll-like receptor (TLR) ligands, miR-146 is persistently increased in keratinocytes, downregulating the expression of inflammatory chemokines including IL-8 and C-C motif chemokine ligand 20 ( 23 ). Consequently, miR-146a decreases TLR-dependent epidermal inflammation via the IL-1 receptor-associated kinase-1 and TNF receptor-associated factor 6 pathways, which mediate the IL-17A signaling to NF-κB and the recruitment of inflammatory cells ( 24 – 27 ) ( Fig. 4 ).…”