In a CD18 hypomorphic polygenic PL/J mouse model, the severe reduction of CD18 (β2 integrin) to 2–16% of wild-type levels leads to the development of a psoriasiform skin disease. In this study, we analyzed the influence of reduced CD18 gene expression on T cell function, and its contribution to the pathogenesis of this disease. Both CD4+ and CD8+ T cells were significantly increased in the skin of affected CD18 hypomorphic mice. But only depletion of CD4+ T cells, and not the removal of CD8+ T cells, resulted in a complete clearance of the psoriasiform dermatitis. This indicates a central role of CD4+ T cells in the pathogenesis of this disorder, further supported by the detection of several Th1-like cytokines released predominantly by CD4+ T cells. In contrast to the CD18 hypomorphic mice, CD18 null mutants of the same strain did not develop the psoriasiform dermatitis. This is in part due to a lack of T cell emigration from dermal blood vessels, as experimental allergic contact dermatitis could be induced in CD18 hypomorphic and wild-type mice, but not in CD18 null mutants. Hence, 2–16% of CD18 gene expression is obviously sufficient for T cell emigration driving the inflammatory phenotype in CD18 hypomorphic mice. Our data suggest that the pathogenic involvement of CD4+ T cells depends on a gene dose effect with a reduced expression of the CD18 protein in PL/J mice. This murine inflammatory skin model may also have relevance for human polygenic inflammatory diseases.

Tumor invasion and metastasis of malignant melanoma have been shown to require proteolytic degradation of the extracellular environment achieved primarily by enzymes of the matrix metalloproteinases (MMP) family. We have earlier shown that increased enzyme activity is localized at the border of tumor cells and the adjacent peritumoral connective tissue, emphasizing the importance of tumor-stroma interactions in the regulation of MMP activity. To confirm the role of stroma-derived MMP-13 in the invasion process, we investigated the invasiveness of melanoma cells upon intradermal injection in mice with complete inactivation of MMP-13. Tumor growth was significantly impaired in mmp-13(-/-) mice and most significant at early time points as compared with wild-type littermates. Moreover, metastasis to various organs was reduced to 17.6 vs 30% in lungs, 2.9 vs 30% in the liver. Strikingly, ablation of MMP-13 completely abrogated formation of metastasis in the heart (0 vs 40%). Notably, decreased tumor growth in mmp-13(-/-) mice was associated with reduced blood vessel density. In addition, decreased blood vessel permeability in the tumors was measured by magnetic resonance imaging of tumor-bearing animals. These data suggest an important role of MMP-13 in tumor growth and an unexpected role in organ-specific metastasis of melanoma cells.

ADAM-9 belongs to a family of transmembrane, disintegrin-containing metalloproteinases (ADAMs) involved in protein ectodomain shedding and cell-cell and cell-matrix interactions. Although the functions of many ADAM family members are known, the specific biological function of ADAM-9 is still unclear. In this study, we have analyzed ADAM-9 temporal and spatial distribution during wound healing. We showed increased ADAM-9 transcript expression during the first 7 days post-wounding and, by immunolocalization, detected ADAM-9 in all migrating and proliferating keratinocytes from days 3 to 7. In older 14-day-old wounds, ADAM-9 expression was restored. We have investigated the role of this protein in the healing process following excisional wounding. Animals deficient in ADAM-9 showed accelerated wound repair compared with control littermates. No alterations in neutrophil, leukocyte, and macrophage infiltration were observed. However, re-epithelialization was significantly faster in Adam-9 -/- than control wounds. Although no differences in proliferation were observed in vivo and in vitro, increased migration of keratinocytes was responsible for this effect. These results show the previously unreported role of ADAM-9 in wound repair by regulating keratinocyte migration through modulation of collagen XVII shedding.

The nucleotide binding and oligomerization domain-like receptor (NLR) protein NLRP10 is highly expressed in the epidermis and contributes to cell-autonomous responses against invasive bacteria. To investigate the role of NLRP10 in inflammatory responses of the skin we analyzed the effect of full-body and keratinocyte-specific depletion of NLRP10 in croton oil-induced irritant contact dermatitis (ICD) and 1-fluoro-2,4-dinitrobenzene (DNFB)-induced contact hypersensitivity (CHS) in mice. Nlrp10 −/− mice were phenotypically normal and skin repair after wounding was not affected by lack of NLRP10. Similarly, we did not detect a contribution of NLRP10 to the ICD response induced by croton oil. In contrast, Nlrp10 −/− mice showed significantly reduced inflammation in the DNFB-induced CHS response as compared to control animals. Microscopic analysis revealed significantly reduced numbers of CD4 + and CD8 + T cells in the infiltrates of animals lacking NLRP10 expression after CHS challenge. Epidermis-specific deletion of Nlrp10 by keratin-14 promotor driven Cre-recombinase was sufficient to account for this phenotype, although lymphocyte recruitment seemed to be unaltered in animals lacking NLRP10 expression in keratinocytes. Taken together, we provide evidence that NLRP10 contributes to T-cellmediated inflammatory responses in the skin and highlight a physiological role of NLRP10 in epidermal keratinocytes.Keywords: Contact dermatitis r Contact hypersensitivity r NLRP10 r Mouse model Additional supporting information may be found in the online version of this article at the publisher's web-site

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