Abstract
Elucidating the poorly defined mechanisms by which inflammatory lesions are spatially restricted in vivo is of critical importance in understanding skin disease. Chemokines are the principal regulators of leukocyte migration and are essential in the initiation and maintenance of inflammation. The membrane-bound psoriasis-associated atypical chemokine receptor 2 (ACKR2) binds, internalizes and degrades most proinflammatory CC-chemokines. Here we investigate the role of ACKR2 in limiting the spread of cutaneous psoriasiform inflammation to sites that are remote from the primary lesion. Circulating factors capable of regulating ACKR2 function at remote sites were identified and examined using a combination of clinical samples, relevant primary human cell cultures, in vitro migration assays, and the imiquimod-induced model of psoriasiform skin inflammation. Localized inflammation and IFN-γ together up-regulate ACKR2 in remote tissues, protecting them from the spread of inflammation. ACKR2 controls inflammatory T-cell chemotaxis and positioning within the skin, preventing an epidermal influx that is associated with lesion development. Our results have important implications for our understanding of how spatial restriction is imposed on the spread of inflammatory lesions and highlight systemic ACKR2 induction as a therapeutic strategy in the treatment and prevention of psoriasis and potentially a broad range of other immune-mediated diseases.
Highlights
Chemokines, the primary in vivo regulators of leukocyte migration, are central to inflammatory pathogenesis (Rot and von Andrian, 2004; Zlotnik and Yoshie, 2000)
The dynamics of psoriasis-like pathology during induction of inflammation was quantified using a modified Psoriasis Area Severity Index (PASI), which showed that atypical chemokine receptor 2 (ACKR2)-deficient mice rapidly develop substantially worse pathology than wild type (WT) mice (Figure 1d)
Our data show that remote up-regulation of ACKR2 occurs by soluble mediators released from inflammatory lesions and that this limits the spread of inflammation to tissues remote to the original lesion
Summary
Chemokines, the primary in vivo regulators of leukocyte migration, are central to inflammatory pathogenesis (Rot and von Andrian, 2004; Zlotnik and Yoshie, 2000). In addition to the classical signaling chemokine receptors (Bachelerie et al, 2014a), there exists a subfamily of stromally expressed atypical chemokine receptors that display promiscuous ligand binding and atypical signaling responses after ligand binding (Bachelerie et al, 2014b; Graham et al, 2012; Nibbs and Graham, 2013) These atypical chemokine receptors can function as chemokine scavengers, thereby. Received 29 March 2016; revised 6 July 2016; accepted 19 July 2016; accepted manuscript published online 26 August 2016; corrected proof published online 24 October 2016 fine-tuning or limiting chemokine responses in vivo One of these molecules, atypical chemokine receptor 2 (ACKR2; previously known as D6), is a high-affinity receptor for multiple inflammatory CC-chemokines (Graham and Locati, 2013). ACKR2’s role in limiting the development of inflammation is shown by numerous studies of ACKR2-deficient mice and by reports of aberrant expression patterns in human inflammatory pathologies (Bazzan et al, 2012; Cochain et al, 2012; Codullo et al, 2011; Singh et al, 2012)
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