The role and regulation of the atypical chemokine receptor 2 in psoriasiform inflammation

Shams, Kave (2017) The role and regulation of the atypical chemokine receptor 2 in psoriasiform inflammation. PhD thesis, University of Glasgow.

Abstract

Psoriasis is a common, debilitating systemic inflammatory disorder that is characterised by sharply demarcated, thick, erythematous scaly skin plaques. Such plaques commonly appear on skin that is subjected to repeated tensile trauma, such as elbows, knees and flexures. The mechanism by which these inflammatory lesions are spatially restricted is not known and yet knowledge of this could be of critical importance for our understanding of this disease. Chemokines are the principal regulators of leukocyte migration and play a critical role in the initiation and maintenance of inflammation. The atypical chemokine receptor ACKR2 (formerly D6) binds inflammatory CC-chemokines, but does not signal upon ligand binding; instead ACKR2 internalises and helps degrade such chemokines, after which it continues to cycle back to the cell surface. ACKR2 acts, through this mechanism, as a high-capacity scavenger of chemokines, and plays an important role in regulating inflammation. It is known that ACKR2 expression is high in unaffected skin in patients with psoriasis (remote from inflammatory plaques) and concurrently deficient in the plaques themselves. Additionally, human studies have shown that simple skin trauma in psoriasis patients causes a reduction in cutaneous ACKR2 expression at the site of trauma. However, the functional significance and the molecular mechanism by which it occurs are not understood. This thesis explored the role of ACKR2 in the spatial restriction of psoriasiform inflammation and the molecular mechanisms for its differential regulation. Through the use of disease relevant mouse models, primary human cell cultures and novel cell migration assays, the results presented here show that localised psoriasiform inflammation upregulates ACKR2 in remote tissues through the systemic release of cytokines. This remotely upregulated ACKR2 expression protects tissues from the further spread of inflammation. This protective effect is mediated by stromally expressed ACKR2 that acts to control inflammatory T-cell positioning within the skin. Tensile trauma of keratinocytes however, acted to reduce ACKR2 expression in the context of inflammation, which in turn provides a novel mechanism for the well-characterised phenomenon that occurs in psoriasis (and a range of skin condition) termed ‘koebnerisation’. Koebnerisation refers to the phenomenon by which relatively simple skin trauma induces the development of disease-specific skin lesions. Furthermore, this thesis defines novel disease-relevant regulators of ACKR2 expression. In silico analyses identified psoriasis-associated microRNAs that bound to the 3’-UTR of ACKR2, and reduced its expression at transcriptional and protein level. Importantly, trauma of keratinocytes induced ACKR2 downregulation concurrent with a substantial and significant increase in the expression of the identified ACKR2 targeting microRNAs. Together, this thesis defines a novel mechanism by which ACKR2-mediated regulation of chemokine function, cutaneous trauma, microRNAs and systemic cytokines, co-ordinately modulate the predisposition of remote tissue sites to the development of new lesions. Importantly, the results presented here have profound implications for how spatial restriction is imposed on inflammation. The data also highlight therapeutic ACKR2 induction as a plausible novel strategy for the limitation and treatment of psoriasiform- and potentially other forms of inflammation.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Keywords: Psoriasis, ACKR2, chemokine, skin, inflammation.
• Subjects: Q Science > QR Microbiology > QR180 Immunology
• Colleges/Schools: College of Medical Veterinary and Life Sciences > School of Infection & Immunity
• Supervisor's Name: Graham, Prof. Gerry and McKimmie, Dr. Clive
• Date of Award: 2017
• Depositing User: Mrs Marie Cairney
• Unique ID: glathesis:2017-8121
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 21 Apr 2017 16:01
• Last Modified: 26 Mar 2019 12:12
• URI: https://theses.gla.ac.uk/id/eprint/8121