**4.1.1 Keratinocytes in psoriasis**

Over the last 20 years it has been regularly discussed if psoriatic skin lesions arise from a primary alteration in epidermal keratinocytes or in T cells (**Figure 1**); the current view is that infiltrating T cells initiate and maintain psoriasis. In this vision, cytokines (e.g., IL-1, IL-6 and IFN-) secreted by T cells and other inflammatory cells (DCs, macrophages and neutrophils) would trigger KCs hyperproliferation, inducing epidermal hyperplasia (J. G. Krueger, 2002). In particular, IL-23, whose expression is increased in psoriatic lesion (Piskin et al., 2006), has been implied in the development of epidermal acanthosis, most likely through the induction of IL-22 (Zheng et al., 2007); injection of IL-23 into mouse dermis induces as dermal inflammation as epidermal hyperplasia similarly to features seen in psoriasis (J. R. Chan et al., 2006).

Previous studies (J. G. Krueger, 2002) suggested an additional explanation for the chronic epidermal hyperplasia in psoriatic lesions: the migration of T cells in the epidermis would firstly break the basement membrane, which has been shown to have large areas with reduced staining intensity for collagen IV and laminins (Fleischmajer et al., 2000), and secondly disrupt desmosome connection between KCs. These two events could be interpreted by KCs as an injury and therefore induce a wound repair response. As a consequence many mitogenic cytokines would be released by KCs triggering a regenerative epidermal growth. Hence, T cells in psoriatic epidermis would be responsible for the chronic hyperplasia as by releasing pro-inflammatory cytokines as by disrupting epidermal integrity.

Another evidence against the fundamental role of T cells in psoriasis arise from the observation that HIV+ patients (which usually have reduced number of CD4+ T cells) develop psoriasis with similar frequency as the rest of the population (Namazi, 2004).

Finally, in 2005 Zenz et al. reported an interesting animal model with psoriasis-like features (Zenz et al., 2005); They knocked out JunB and c-Jun, two components of the AP-1 transcription factor, which control cell proliferation and differentiation , cytokine production, and stress responses in the skin. The importance of this animal model lies in the fact that JunB is located in the PSORS6 locus, which has been shown to be a psoriasis susceptibility region (Hensen et al., 2003). Interestingly, these mice developed not only inflammatory skin lesions but also a form of destructive arthritis. This evidence suggested that alteration in the epidermal Jun-pathway may be sufficient to induce inflammatory reactions in the skin as well as in the joints. At the skin level these mice showed typical hallmarks of psoriasis: hyperkeratosis, enlarged blood vessels, infiltration of T cells and neutrophils, and up-regulation of pro-inflammatory cytokines.

The most intriguing aspect was the examination of the T cells role in development of psoriasis in a genetic model: upon deletion of JunB and c-Jun proteins in Rag2-deficient mice (mice deficient of T/B cells), skin changes like in psoriasis were still induced, though they were milder. These data suggest a minor role for T cells in the etiology of psoriasis-form skin inflammation, and that primary alterations in KCs were sufficient to drive psoriasisform changes in the mice skin. But before stating that KCs instigate psoriasis in humans, the relevance of this model must be discussed further. A recent study (Haider et al., 2006) showed that the JunBwas expression increased in psoriatic plaques instead of decreased/deleted as in the Zenz mouse model, suggesting a role for JunB as a transcriptional activator of disease-related genes in psoriatic KCs.

The ongoing discussion about the primary instigator of psoriasis reflects the complexity of this disease and the still elusive interplay between KCs and immune cells in driving psoriasis.

This problem was further addressed in a another mouse model, in which STAT-3 was constitutively activated in basal KCs under the control of the keratin 5 promoter (K5.Stat3C) (Sano et al., 2005). As in human psoriatic plaques, induced lesions of K5.Stat3C mice shown a considerable number of CD4+ T and CD8+ T cells in the epidermis. For psoriasis development, this model required both activated STAT-3 in KCs and activated T cells in the dermis and epidermis of the transgenic rodents, suggesting the theory that KCs and T cells could act together in psoriasis pathogenesis.
