Chronic Proliferative Dermatitis in Mice: NFκB Activation Autoinflammatory Disease

Abstract

Autoinflammatory diseases are a heterogeneous group of congenital diseases characterized by the presence of recurrent inflammation, in the absence of infectious agents, detectable autoantibodies or antigen-specific autoreactive T-cells. SHARPIN deficient mice presents multiorgan chronic inflammation without known autoantibodies or autoreactive T-cells, designated Sharpincpdm. Histological studies demonstrated epidermal hyperproliferation, Th-2 inflammation, and keratinocyte apoptosis in this mutant. The mutant mice have decreased behavioral mobility, slower growth, and loss of body weight. Epidermal thickness and mitotic epidermal cells increase along with disease development. K5/K14 expression is distributed through all layers of epidermis, along with K6 expression in interfollicular epidermis, suggesting epidermal hyperproliferation. K1/K10 is only detectable in outer layers of spinosum epidermis, reflecting accelerated keratinocyte migration. Alpha smooth muscle actin is overexpressed in skin blood vessels, which may release the elevated white blood cells to dermis. CD3+CD45+ cells and granulocytes, especially eosinophils and mast cells, aggregate in the mutant skin. TUNEL assay, together with Annexin-V/propidium iodide FACS analysis, confirmed the increase of apoptotic keratinocytes in skin. These data validate and provide new lines of evidence of the proliferation-inflammation-apoptosis triad in Sharpincpdm mice, an NFκB activation autoinflammatory disease.

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

“…IFN-g-mediated increase of HOIP and HOIL-1L-protected cpdm cells from TNF-a-mediated apoptosis both in vitro and in vivo cpdm mice are spontaneous mutant mice lacking SHARPIN (15,29). As observed in the WT cells, IFN-g increased the expression of HOIP and HOIL-1L mRNA in MEFs from cpdm mice ( Fig.…”

“…Although the precise mechanism underscoring chronic dermatitis in cpdm mice has not been clarified yet, both TNF-a and increased keratinocyte apoptosis have been suggested to be involved in the pathogenesis of dermatitis (16,29). Because we observed that IFN-g protects cpdm keratinocytes from TNF-a-induced apoptosis and activates NF-kB both in vitro and in vivo, we injected IFN-g once a day into the back of cpdm mice for 3 wk to evaluate the effect of IFN-g on the severity of cpdm dermatitis.…”

“…Discussion cpdm mice are characterized by various symptoms including chronic proliferative dermatitis (15,29). Because of the lack of SHARPIN, the amount of the other two subunits of LUBAC is drastically reduced in cpdm mice.…”

Integrin beta 1 inhibition alleviates the chronic hyperproliferative dermatitis phenotype of SHARPIN-deficient mice

“…Chronic inflammation in Sharpin cpdm/cpdm mice is characterized by enhanced infiltration of immune cells to many tissues including the skin [ 1 , 29 ], as well as increased numbers of white blood cells in the peripheral blood [ 30 ]. Interestingly, leukocyte (CD45 + ; Fig 3A and 3B ), macrophage (F4/80 + ; Fig 3C and 3D ) and mast cell (Toluidine blue + ; Fig 3E and 3F ) infiltration into the dermis of Sharpin cpdm/cpdm mice was not affected by the Itgb1 function-blocking antibody, indicating that inflammation was not reduced.…”

SIPL1 enhances the proliferation, attachment, and migration of CHO cells by inhibiting PTEN function

“…Additionally, SIPL1 is involved in the inside-out activation of β1-integrin through direct binding to the α-integrin subunit (19). Loss of SIPL1 expression is also a causative factor of the chronic proliferative dermatitis (CPDM) phenotype in mice as a result of abnormal activation of NF-κB (20)(21)(22).…”