IL‐22 binding protein regulates murine skin inflammation

Abstract

IL22RA2 gene expression in human skin was higher in the epidermal compartment of the skin in comparison with dermis in both healthy skin and psoriasis skin ( Figure 2B). When comparing expression in samples from healthy controls, psoriasis non-affected skin and psoriasis lesions, a trend towards lower epidermal IL22RA2 expression was noted in lesional psoriasis compared to controls or non-lesional psoriasis in line with the data obtained from imiquimod-treated murine skin.However, this trend did not reach statistical significance. | CONCLUSIONSTargeting the IL-22 system has therapeutic potential for several diseases, of which psoriasis is one of the most promising.[9] An IL-22 neutralizing antibody (ILV-094) has been tested in a phase I study for moderate-to-severe chronic plaque psoriasis (ClinicalTrials.gov identifier: NCT00563524). However, this project is now discontinued apparently due to the lack of response. Other interventions in the IL-22 system, such as targeting of the IL-22R, may be more successful and an appreciation for the role of IL-22BP, the third player in the IL-22-IL-22R system, will benefit such endeavours. We here show that IL-22BP limits the pathological manifestations in mouse models of allergic contact dermatitis and psoriasis and, in the latter, has an important role in restraining, chemokine expression, T-cell activation and neutrophil recruitment.

Limited Presence of IL-22 Binding Protein, a Natural IL-22 Inhibitor, Strengthens Psoriatic Skin Inflammation

“…The cellular and molecular mechanisms of this decrease nevertheless still remain to be understood. When preparing this manuscript, a report appeared in which IL-22BP expression was analyzed specifically in epidermis and dermis of skin biopsies from psoriasis patients (47). In contrast to our study, the authors did not observe any difference in both compartments between healthy donors and nonlesional skin of psoriasis patients (47).…”

“…We first showed that, in comparison with littermate controls, a constitutive deficiency of IL-22BP in Il22ra2 2/2 rats was associated with increased severity of the disease because of unleashed actions of IL-22, as further confirmed by enhanced expression of known IL-22-inducible genes in the lesional skin. These data confirm a recently accepted publication showing the same model of skin inflammation in Il22ra2 2/2 mice (47). Importantly, we further corroborated these data by performing for the first time, to our knowledge, a pharmacological blockade of endogenous IL-22BP through injecting a neutralizing Ab (28) to imiquimod-treated mice and thus recapitulating our observations made in IL-22BP-deficient rats.…”

“…When preparing this manuscript, a report appeared in which IL-22BP expression was analyzed specifically in epidermis and dermis of skin biopsies from psoriasis patients (47). In contrast to our study, the authors did not observe any difference in both compartments between healthy donors and nonlesional skin of psoriasis patients (47). The reason for this discrepancy is unclear but might be due to the long-lasting and stressing procedure the authors used in their study to separate the epidermis from the dermis, which may have altered mRNA expressions and masked any possible preexisting differences.…”

IL-22 Binding Protein Promotes the Disease Process in Multiple Sclerosis

“…A relatively physiological way to characterize the effects of IL-22 is to manipulate the levels of IL-22BP in animal disease models. We and others have shown that IL-22BP acts to limit inflammation in models of psoriasis and inflammatory bowel disease, both affecting barrier surfaces (15,16). In contrast, we have also shown that both rats with a natural genetic variant in this locus that confers lower expression of IL-22BP and mice with full gene deletion have less severe disease in an animal model of MS (17,18).…”

Microbiota-Dependent Effects of IL-22

“…IL-22BP is significantly downregulated in skin biopsies taken from psoriasis patients in comparison to healthy controls [ 98 ]. Conforming to what is understood about the workings of the IL-22/IL-22BP axis, it has been further demonstrated that IL-22BP acts in a protective manner in skin-related conditions, as reported in mouse models of psoriasis and atopic dermatitis [ 98 , 99 , 100 ]. Nevertheless, the mechanisms regulating the production of IL-22BP from different cellular sources and, in particular, in response to skin infections is yet to be elucidated.…”