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

Abstract

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. We reveal that immunoglobulin superfamily member CD200, and signalling via its receptor, CD200R1 are reduced in non-lesional psoriasis skin. To examine the consequences of this, CD200R1 was blocked in a mouse model of psoriasis demonstrating that the receptor limits psoriasis-like inflammation. Specifically, CD200R1 blockade enhances 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. Collectively, our 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 a pathway that might be targeted to dampen inflammation in patients with psoriasis.

CD200R1 promotes IL-17 production by ILC3s, by enhancing STAT3 activation

“…Indeed, the skin thickening in response to psoriasis-like inflammation was not changed in CD200R1-deficient mice despite the reduction in IL-17A, which suggests that there may be an increase in an alternative inflammatory response in these mice. The fact that we did not observe a decrease in IL-17A production in psoriasis-like skin inflammation when CD200R1 was blocked in adult skin (17), supports our findings here that the role for CD200R1 promoting IL-17A production, is during an earlier development stage, perhaps in neonates when ILCs develop and seed peripheral tissues.…”

“…As we (17) and others (18) have demonstrated reduced CD200 levels in psoriatic patient samples, and CD200R1 signalling has been shown to dampen immune responses (7–13), we hypothesized that the absence of CD200R1 would enhance inflammation in psoriasis models. Contrary to this, global CD200R1KO deficiency protected mice from skin thickening in a model induced by repeated intradermal injection with IL-23 (19) (Figure 1A and B).…”

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

“…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.…”

“…CD200R1 is a cell surface receptor which on engagement with its ligand, CD200, transmits a signalling cascade inhibiting MAP 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 (14–17), however its function on these cells remains underexplored.…”