Therapeutic interventions in mice with chronic proliferative dermatitis (cpdm/cpdm)

Abstract

Chronic proliferative dermatitis (cpd) is a spontaneous mutation in C57BL/Ka mice (cpdm/cpdm). The dermatitis is characterized by redness, hairloss, scaling, pruritus and histologically by epithelial hyperproliferation, infiltration of eosinophils, macrophages and mast cells. Lesions similar to those in the skin occur in the esophagus and forestomach. In this paper, we describe the effect of drug treatments directed against epidermal hyperproliferation (calcipotriene and etretinate), against inflammation (corticosteroids and dapsone) and against pruritus (loratidine and capsaicin). The criteria used to objectively estimate the effect of the treatment were 1) macroscopic evaluation of the lesions (cpd score), 2) degree of epithelial hyperproliferation assessed by BrdU incorporation and epithelial thickness, and 3) microscopic evaluation of the inflammatory cells in the skin samples. Treatment of the cpdm/cpdm mice with calcipotriene (5 microg/day for 3 weeks) inhibited epidermal proliferation and the number of eosinophils. Systemic etretinate treatment (30 microg/g/day for 3 weeks) was not very effective. Topical corticosteroids (0.05 microg/day, for 3 weeks) exerted a therapeutic effect on the hyperproliferation and the number of eosinophils. Oral dapsone treatment (34 microg/g/day, for 5 weeks) reduced the BrdU incorporation in the skin and the epithelial thickness in the esophagus. The anti-histamine loratidine (orally, 1.7 microg/ g/day, for 4 weeks) reduced the severity of the lesions macroscopically, probably by suppressing the pruritus. Capsaicin (topically, 30 mM, for 5 weeks) also reduced the severity of the macroscopic observable lesions. Moreover, capsaicin reduced the dorsal and ventral epidermal thickness. The results from this and previous studies indicate that steroids (topically and systemically) and less strongly calcipotriene are the most effective treatments for the lesions observed in the cpdm/cpdm mice, since both hyperproliferation and the influx of eosinophils are reduced. Although the pathogenesis of the cpd lesions remains to be determined, our results indicate that the cpdm/cpdm mouse can be used to investigate new drugs for their possible application in chronic dermatitis.

IFN-γ or IFN-α Ameliorates Chronic Proliferative Dermatitis by Inducing Expression of Linear Ubiquitin Chain Assembly Complex

“…Infiltration of inflammatory cells into the affected skin has been reported in cpdm mice (14). We confirmed that neutrophils (Gr-1 + ), macrophages (F4/80 + ), and T cells (CD3 + and CD4 + ) infiltrated Fig.…”

“…4H). An increase in the number of proliferative keratinocytes is another characteristic of cpdm dermatitis (14,15). Keratinocytes expressing the proliferation markers Ki67 and Keratin 6 were decreased in IFN-g-treated mice, as compared with PBS-treated mice (Fig.…”

“…LUBAC is composed of HOIL-1L-interacting protein (HOIP), heme-oxidized IRP2 ubiquitin ligase-1L (HOIL-1L), and SHANK-associated RH domain protein (SHARPIN). Lack of SHARPIN causes chronic proliferative dermatitis (cpdm) in cpdm mice, which exhibit systemic chronic inflammation including dermatitis, arthritis, and esophagitis (14,15).…”

Spontaneous mutations in the mouse Sharpin gene result in multiorgan inflammation, immune system dysregulation and dermatitis

“…Female cpdm/cpdm mice are infertile, 7 and mutant colonies were maintained by mating homozygous male  heterozygous female, or heterozygote  heterozygote. Normal littermate controls were wild type as determined by test matings or sequencing of DNA, or heterozygotes, as indicated.…”

The Inflammatory Caspases-1 and -11 Mediate the Pathogenesis of Dermatitis in Sharpin-Deficient Mice

“…Interestingly, mice deficient in the different LUBAC components display radically different phenotypes; Hoil1 2/2 mice are viable and phenotypically normal (28), Hoip 2/2 mice die during embryogenesis at midgestation (29), and a homozygous inactivating mutation in Sharpin triggers development of severe multiorgan inflammation, with the most prominent feature being chronic proliferative dermatitis (cpdm) (30)(31)(32)(33). Sharpin cpdm/cpdm mice display skin lesions with traits similar to AD and psoriasis in humans, such as hyperkeratosis, acanthosis, dermal spongiosis, and keratinocyte apoptosis (19,34). Along with dermatitis, cpdm mice develop systemic inflammation and adaptive immune defects, such as splenomegaly, disrupted secondary lymphoid organ development, and inflammatory infiltrates throughout the body.…”