Psoriasis is a common, relapsing inflammatory skin disease characterized by erythematous scaly plaques. Histological manifestations of psoriasis include keratinocyte dysregulation and hyperproliferation, elongated rete ridges, and inflammatory infiltrates consisting of T cells, macrophages, dendritic cells, and neutrophils. Despite the availability of new effective drugs to treat psoriasis, the underlying mechanisms of pathogenesis are still poorly understood. Recent studies have shown that Aldara cream, used to treat benign skin abnormalities, triggers psoriasis-like disease in humans and mice and have implicated Th17 cells in disease initiation. Using this as a model, we found a predominant role for the Th17 signature cytokines IL-17A, IL-17F, and IL-22 in psoriasiform plaque formation in mice. Using gene-targeted mice, we observed that loss of Il17a, Il17f, or Il22 strongly reduced disease the severity of psoriasis. However, we found that Th17 cells were not the primary source of these pathogenic cytokines. Rather, IL-17A, IL-17F, and IL-22 were produced by a skin-invading population of γδ T cells and RORγt + innate lymphocytes. Furthermore, our findings establish that RORγt + innate lymphocytes and γδ T cells are necessary and sufficient for psoriatic plaque formation in an experimental disease model that closely resembles human psoriatic plaque formation.

Psoriasis is an autoinflammatory skin disease of unknown etiology. Topical application of Aldara cream containing the Toll-like receptor (TLR)7 agonist Imiquimod (IMQ) onto patients induces flares of psoriasis. Likewise, in mice IMQ triggers pathological changes closely resembling psoriatic plaque formation. Key cytokines like IL-23 and type-I IFN (IFN-I), both being produced mainly by dendritic cells (DCs), have been implicated in psoriasis. Although plasmacytoid DCs (pDCs) are the main source of IFNα and thought to initiate disease, conventional DCs (cDCs) appear to maintain the psoriatic lesions. Any role of cDCs during lesion formation remains elusive. Here, we report that selective activation of TLR7 signaling specifically in CD11c + DCs was sufficient to induce psoriasiform skin disease in mice. Intriguingly, both pDCs and the IFN-I pathway were dispensable for the development of local skin inflammation. Selective TLR7 triggering of Langerin + DCs resulted in attenuated disease, whereas their depletion did not alter the severity of skin lesions. Moreover, after IMQ-painting, IL-23 was exclusively produced by Langerin neg DCs in vivo. In conclusion, TLR7-activated Langerin neg cDCs trigger psoriatic plaque formation via IL-23-mediated activation of innate IL-17/IL-22-producing lymphocytes, independently of pDCs or IFN-I. These results suggest therapeutic targeting of IL-23 production by cDCs to refine current treatment strategies for psoriasis.

Inflammatory disorders of the CNS are frequently accompanied by synaptic loss, which is thought to involve phagocytic microglia and complement components. However, the mechanisms accounting for aberrant synaptic connectivity in the context of CD8 T cell-driven neuronal damage are poorly understood. Here, we profiled the neuronal translatome in a murine model of encephalitis caused by CD8 T cells targeting antigenic neurons. Neuronal STAT1 signaling and downstream CCL2 expression were essential for apposition of phagocytes, ensuing synaptic loss and neurological disease. Analogous observations were made in the brains of Rasmussen's encephalitis patients. In this devastating CD8 T cell-driven autoimmune disease, neuronal STAT1 phosphorylation and CCL2 expression co-clustered with infiltrating CD8 T cells as well as phagocytes. Taken together, our findings uncover an active role of neurons in coordinating phagocyte-mediated synaptic loss and highlight neuronal STAT1 and CCL2 as critical steps in this process that are amenable to pharmacological interventions.

Neutralization of the common p40-subunit of IL-12/23 in psoriasis patients has led to a breakthrough in the management of moderate to severe disease. Aside from neutralizing IL-23, which is thought to be responsible for the curative effect, anti-p40 therapy also interferes with IL-12 signalling and type 1 immunity. Here we dissect the individual contribution of these two cytokines to the formation of psoriatic lesions and understand the effect of therapeutic co-targeting of IL-12 and IL-23 in psoriasis. Using a preclinical model for psoriatic plaque formation we show that IL-12, in contrast to IL-23, has a regulatory function by restraining the invasion of an IL-17-committed γδT (γδT17) cell subset. We discover that IL-12 receptor signalling in keratinocytes initiates a protective transcriptional programme that limits skin inflammation, suggesting that collateral targeting of IL-12 by anti-p40 monoclonal antibodies is counterproductive in the therapy of psoriasis.

Conventional αβ T cells have the ability to form a long-lasting resident memory T-cell (T RM ) population in nonlymphoid tissues after encountering foreign antigen. Conversely, the concept of 'innate memory', where the ability of nonadaptive branches of the immune system to deliver a rapid, strengthened immune response upon reinfection or rechallenge, is just emerging. Using the αβ T-cell-independent Aldara psoriasis mouse model in combination with genetic fate-mapping and reporter systems, we identified a subset of γδ T cells in mice that is capable of establishing a long-lived memory population in the skin. IL-17A/F-producing Vγ4 Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionPsoriasis is an immune-mediated skin disease, with a relapsing and remitting nature. It affects approximately 2-3% of the world's population [1,2]. Despite rarely being life-threatening, psoriasis has a negative effect on the life expectancy of the sufferers of approximately 3.5 years in males and 4.4 years in females [3,4]. Moreover, the high morbidity in psoriasis patients results in its burden on the economy being comparable to diabetes, cardiovascular diseases, and CNS illnesses [5,6]. Psoriasis is generally limited to inflammation of the skin, but as many as 30% of the patients also suffer from debilitating psoriatic arthritis, while the Correspondence: Prof. Burkhard Becher e-mail: becher@immunology.uzh.ch general population has a prevalence of around 1% [2]. Psoriasis has many well-established comorbidities, in particular cardiovascular diseases [2,7], Crohn's disease [1,4], type II diabetes [3,6], obesity [2,5], metabolic syndrome [8], and lymphoma [9]. The exact mechanism of psoriasis pathogenesis is still poorly understood. Complicating matters further is the dynamic nature of psoriasis, which makes it likely that different cell types play different roles during initiation, progression, maintenance, and remission of the disease [2]. Much of what we have learned about the pathogenesis of psoriasis stems from preclinical model systems [10]. The Aldara model of psoriasis [11] has recently become increasingly popular [12]. It is based on clinical observations that * These authors contributed equally to this work.C 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2015. 45: 3022-3033 HIGHLIGHTS 3023 topical treatment with Aldara cream, for unrelated conditions, could trigger and/or cause relapses of psoriasis in patients [13][14][15][16][17]. Moreover, it replicates the key features of the human disease and even the cytokine profile with abundant amounts of [19][20][21][22]20]. Accordingly, the production of IL-23 by DCs [18,21] and efficacy of the antibody to were also observed in Aldara-treated mice. In the Aldara model, the primary source of IL-17 and IL-22 was shown to be not T H 17 cells but γδ T cells [18][19][20]22]. Moreover, mice deficient for γδ T cells developed a drastically reduced disease [18,19]. The func...