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

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.

CD200R1 promotes interleukin-17 production by group 3 innate lymphoid cells by enhancing signal transducer and activator of transcription 3 activation

“…As we 17 and others 18 have demonstrated reduced CD200 levels in samples from patients with psoriasis and CD200R1 signaling has been shown to dampen immune responses, 7 , 8 , 9 , 10 , 11 , 12 , 13 we hypothesized that the absence of CD200R1 would enhance inflammation in psoriasis models. Contrary to this, global CD200R1 deficiency protected mice from skin thickening in a model induced by repeated intradermal injection with IL-23 19 ( Figs.…”

“…We have previously shown that the ligand CD200 is reduced in nonlesional psoriatic skin 17 and we therefore hypothesized that in healthy skin, CD200R1 signaling prevents inappropriate inflammation; however, in psoriasis, this is reduced, contributing to psoriasis susceptibility. To examine this hypothesis, here, we compare the severity of inflammation in psoriasis models in wild-type (WT) and CD200R1-deficient mice.…”

“… 13 CD200R1 is a cell surface receptor, which on engagement with its ligand, CD200, transmits a signaling cascade inhibiting mitogen-activated protein kinases and suppressing myeloid cell activation. CD200R1 is expressed on many immune cell types, and in addition to myeloid cells, is particularly highly expressed on ILC 14 , 15 , 16 , 17 ; however, its function on these cells remains underexplored.…”

Serum LL‐37 and inflammatory cytokines levels in psoriasis

“…Recently, diagnosis of PsO mainly depends on the assessment of medical history and clinical signs by trained dermatologists, which requires the collaboration of a specialized and trained dermatologist, laboratory technician, and dermatopathologist. To better diagnose and treat PsO, a wide range of biomarkers and targets have been investigated 10–12 . Inflammatory‐related mediators such as IL‐17A, IL23A, and TNF‐α have been reported to be important biomarkers for disease activity of PsO 2,10 .…”

“…To better diagnose and treat PsO, a wide range of biomarkers and targets have been investigated. [10][11][12] Inflammatory-related mediators such as IL-17A, IL23A, and TNF-α have been reported to be important biomarkers for disease activity of PsO. 2,10 Based on the pathological process of PsO, targeting related signaling pathways and molecules can be an effective way to develop therapeutic drugs.…”