Abstract
Dysregulation of interleukin-22 (IL-22) has been associated with autoimmune diseases but divergent effects upon inflammation have hampered efforts to define its contribution to pathogenesis. Here, we examined the role of IL-22 in patients with psoriatic arthritis (PsA). In the peripheral blood of PsA patients, there was a decrease in IL-22+CD4+ T cells compared with healthy controls resulting in a heightened CD4+ IFNγ+/IL-22+ ratio accompanied by diminished CCR6 expression. IL-22 expressing cells were depleted primarily from the central memory CD4 T-cell subset in PsA patients. Paradoxically IL-22 and particularly interferon-gamma (IFNγ) production were elevated within a CD4+ T-cell subset with phenotypic markers characteristic of naïve T cells (CD3+CD4+CD27+CD45RA+CCR7+CD95−IL-2Rβ−) from PsA patients with the highest IFNγ+/IL-22+ ratio of all the CD4 subsets. These unconventional “naïve” CD4+ T cells from PsA patients displayed some phenotypic and functional characteristics of memory cells including a marked proliferative response. Increased IFNγ production from these unconventional “naïve” T cells from PsA patients promoted greater expression of the chemo-attractant CXCL9 by HaCaT keratinocytes compared with their healthy counterparts. Treatment with anti-TNF therapy reversed these abnormalities in this T-cell subset though did not affect the frequency of IL-22+ T cells overall. Furthermore, blockade of IL-22 enhanced the IFNγ mediated release of CXCL-9. These results reveal CD4+ T-cell dysregulation in patients with PsA which can be reversed by anti-TNF and highlight the regulatory properties of IL-22 with important implications for therapeutic approaches that inhibit its production.
Highlights
Psoriatic arthritis (PsA) is an inflammatory arthritis associated with psoriasis [1]
The frequency of CD4+IL-22+ T cells was less in psoriatic arthritis (PsA) compared with healthy controls irrespective of therapy including with the TNF inhibitor adalimumab (Figure 1A)
The percentage of CD4+IFNγ+ T cells was similar between PsA patients and healthy controls (Figure 1C) resulting in an increased ratio of IFNγ:IL-22 in CD4+ T cells in PsA compared with healthy controls (Figure 1D)
Summary
Psoriatic arthritis (PsA) is an inflammatory arthritis associated with psoriasis [1]. TNF-α and IL-17 axis have been implicated in the pathogenesis of psoriasis and PsA [2, 3], there is a stronger IL-17 signature in the skin compared with the synovium [4]. Serum levels of a variety of cytokines including TNF, IL-17, and IL-22 have been positively correlated with psoriasis and PsA though the results have not always been consistent [5,6,7,8,9]. IL-22 promotes keratinocyte proliferation, disrupts normal keratinocyte differentiation, and acts in concert with IL-17 to release pro-inflammatory cytokines and chemokines [2]. Less is known about its role in inflamed joints of PsA
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