Reduced cutaneous CD200:CD200R1 signaling in psoriasis enhances neutrophil recruitment to skin

Linley, Holly and Jaigirdar, Shafqat and Mohamed, Karishma and Griffiths, Christopher E.M. and Saunders, Amy (2022) Reduced cutaneous CD200:CD200R1 signaling in psoriasis enhances neutrophil recruitment to skin. Immunity, Inflammation and Disease, 10 (7). ISSN 2050-4527

Abstract

Introduction: The skin immune system is tightly regulated to prevent inappropriate inflammation in response to harmless environmental substances. This regulation is actively maintained by mechanisms including cytokines and cell surface receptors and its loss results in inflammatory disease. In the case of psoriasis, inappropriate immune activation leads to IL-17-driven chronic inflammation, but molecular mechanisms underlying this loss of regulation are not well understood. Immunoglobulin family member CD200 and its receptor, CD200R1, are important regulators of inflammation. Therefore, we determined if this pathway is dysregulated in psoriasis, and how this affects immune cell activity. Methods: Human skin biopsies were examined by quantitative polymerase chain reaction, flow cytometry, and immunohistochemistry. The role of CD200R1 in regulating psoriasis-like skin inflammation was examined using CD200R1 blocking antibodies in mouse psoriasis models. CD200R1 blocking antibodies were also used in an in vivo neutrophil recruitment assay and in vitro assays to examine macrophage, innate lymphoid cell, γδ T cell, and neutrophil activity. Results: We reveal that CD200 and signaling via CD200R1 are reduced in non-lesional psoriasis skin. In mouse models of psoriasis CD200R1 was shown to limit psoriasis-like inflammation by enhancing acanthosis, CCL20 production and neutrophil recruitment, but surprisingly, macrophage function and IL-17 production were not affected, and neutrophil reactive oxygen species production was reduced. Conclusion: Collectively, these data show that CD200R1 affects neutrophil function and limits inflammatory responses in healthy skin by restricting neutrophil recruitment. However, the CD200 pathway is reduced in psoriasis, resulting in a loss of immune control, and increased neutrophil recruitment in mouse models. In conclusion, we highlight CD200R1:CD200 as a pathway that might be targeted to dampen inflammation in patients with psoriasis.