CD4+ T Cell-Associated Pathophysiology Critically Depends on CD18 Gene Dose Effects in a Murine Model of Psoriasis

Abstract

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.

Targeting NF-κB with a Natural Triterpenoid Alleviates Skin Inflammation in a Mouse Model of Psoriasis

“…To assess the inhibition of NF-B activation by AK␤BA liposomes or PBS liposomes, we sampled the injected skin areas 24 h after treatment. To evaluate the severity of the psoriasiform phenotype, an adapted psoriasis activity and severity index (PASI) score (27) was used for affected CD18 hypo mice before and after treatment with AK␤BA or ␥-CD or PBS liposome controls.…”

Reduction of CD18 Promotes Expansion of Inflammatory γδ T Cells Collaborating with CD4+ T Cells in Chronic Murine Psoriasiform Dermatitis

“…hypo PL/J model has proved to be particularly useful because its skin pathology closely resembles human psoriasis histologically, clinically, and in its polygenic base as previously described (30)(31)(32)(33). Notably, reduced or altered expression of CD18 itself or of the b 2 integrin ligands ICAM-1 and -2, located in proximity to PSORS6 on 19p13 and PSORS2 on 17q25, respectively, may also affect susceptibility to psoriasis in humans, underlining the clinical relevance of the CD18 hypo PL/J psoriasis model (33)(34)(35)(36)(37)(38)(39).…”

“…To further evaluate the function of gd T cells in psoriasiform skin disease, in this investigation we used the CD18 hypomorphic PL/J mouse model (26)(27)(28)(29)(30)(31)(32)(33), an established model of psoriasis on the PL/J background with reduction of CD18/b 2 integrin (Itgb2) levels to 2-16% of wild-type levels due to a hypomorphic CD18 allele (CD18 hypo PL/J mouse), which offers the possibility to analyze T cell subsets in lesional skin and lymph nodes at different disease stages. Compared to IL-23-or IMQ-induced transient skin inflammation mediated selectively via the IL-23-or type I IFN-arm of the inflammatory cascade, leading to a transient psoriasiform disease, the CD18 hypo PL/J psoriasis model is likely more physiological to study non-drug-induced psoriasis for a number of reasons: CD18 hypo PL/J mice commonly develop a spontaneous, chronic, T cell-mediated psoriasiform skin disease around weeks 12-14 after birth due to reduced CD18 expression on a number of immune cell types relevant to human psoriasis (26,27).…”

In Vivo and In Vitro Models of Psoriasis

“…This model shows a decreased expression of the common 2 chain of the leukointegrin adhesion molecule complex (Danilenko, 2008). Beta2 integrins are leukocyte adhesion molecules exclusively expressed on hematopoietic cells and are responsible for cell-cell contacts in a variety of inflammatory interactions (Kess et al, 2003). When the CD18 mutation was crossed onto the PL/J strain of mice, it developed a psoriasiform inflammatory skin condition with a predominantly lymphocyte infiltration (Bullard, et al, 1996).…”

“…Targeting the immune system HLA-B27/ 2 microglobulin rat + + + + (Breban, et al, 1996;Keith, et al, 2005) Hypomorphic CD18 + + + + (Bullard, et al, 1996;Kess, et al, 2003) E (CD103) + + ? + (Schon et al, 2000) K14/p40 + ?…”