Increased expression of chemokines in the skin of chronic proliferative dermatitis mutant mice

Renninger, Matthew L.; Seymour, Rosemarie; Lillard, James W.; Sundberg, John P.; HogenEsch, Harm

doi:10.1111/j.1600-0625.2005.00378.x

Cited by 8 publications

(6 citation statements)

References 49 publications

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“…CCL 11 (eotaxin) and CCL24 (eotaxin-2) are important eosinophil-specific chemokines induced by IL4 and IL13 [19]. We previously documented increased expression of CCL11 in the skin of Sharpin cpdm mice [20]. Here the expression of CCL11 and CCL24 was assessed in Sharpin cpdm-Dem , Il4ra −/− mice to determine if expression is affected by the absence of IL4 and IL13 signaling.…”

Section: Resultsmentioning

confidence: 97%

Chronic Proliferative Dermatitis in Sharpin Null Mice: Development of an Autoinflammatory Disease in the Absence of B and T Lymphocytes and IL4/IL13 Signaling

et al. 2014

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SHARPIN is a key regulator of NFKB and integrin signaling. Mice lacking Sharpin develop a phenotype known as chronic proliferative dermatitis (CPDM), typified by progressive epidermal hyperplasia, apoptosis of keratinocytes, cutaneous and systemic eosinophilic inflammation, and hypoplasia of secondary lymphoid organs. Rag1−/− mice, which lack mature B and T cells, were crossed with Sharpin−/− mice to examine the role of lymphocytes in CDPM. Although inflammation in the lungs, liver, and joints was reduced in these double mutant mice, dermatitis was not reduced in the absence of functional lymphocytes, suggesting that lymphocytes are not primary drivers of the inflammation in the skin. Type 2 cytokine expression is increased in CPDM. In an attempt to reduce this aspect of the phenotype, Il4ra−/− mice, unresponsive to both IL4 and IL13, were crossed with Sharpin−/− mice. Double homozygous Sharpin−/−, Il4ra−/− mice developed an exacerbated granulocytic dermatitis, acute system inflammation, as well as hepatic necrosis and mineralization. High expression of CHI3L4, normally seen in CPDM skin, was abolished in Sharpin−/−, Il4ra−/− double mutant mice indicating the crucial role of IL4 and IL13 in the expression of this protein. Cutaneous eosinophilia persisted in Sharpin−/−, Il4ra−/− mice, although expression of Il5 mRNA was reduced and the expression of Ccl11 and Ccl24 was completely abolished. TSLP and IL33 were both increased in the skin of Sharpin−/− mice and this was maintained in Sharpin−/−, Il4ra−/− mice suggesting a role for TSLP and IL33 in the eosinophilic dermatitis in SHARPIN-deficient mice. These studies indicate that cutaneous inflammation in SHARPIN-deficient mice is autoinflammatory in nature developing independently of B and T lymphocytes, while the systemic inflammation seen in CPDM has a strong lymphocyte-dependent component. Both the cutaneous and systemic inflammation is enhanced by loss of IL4 and IL13 signaling indicating that these cytokines normally play an anti-inflammatory role in SHARPIN-deficient mice.

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Section: Resultsmentioning

confidence: 97%

Chronic Proliferative Dermatitis in Sharpin Null Mice: Development of an Autoinflammatory Disease in the Absence of B and T Lymphocytes and IL4/IL13 Signaling

et al. 2014

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“…The spontaneous Sharpin cpdm/cpdm null mice developed a persistent dermatitis associated with increased expression of T H 2 cytokines, chitinase-like 3 protein (CHIL3), a sensitive marker of alternatively activated macrophages, and eosinophil-specific chemokines [ 4 , 48 ]. The type 2 inflammation may result from lack of SHARPIN in stromal cells, immune cells, or both.…”

Section: Resultsmentioning

confidence: 99%

“…The expression of mRNA in the skin of 4-week old mice was determined by qRT-PCR [48]. Skin from 4 weeks of age/sex matched mice was collected and stored in RNALater (Qiagen, Valencia, CA) at -80˚C until samples from all replicates were collected.…”

Section: Quantitative Real-time Rt-pcr (Qrt-pcr) To Genotype For Sharpinmentioning

confidence: 99%

Keratinocyte-specific deletion of SHARPIN induces atopic dermatitis-like inflammation in mice

et al. 2020

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Spontaneous mutations in the SHANK-associated RH domain interacting protein (Sharpin) resulted in a severe autoinflammatory type of chronic proliferative dermatitis, inflammation in other organs, and lymphoid organ defects. To determine whether cell-type restricted loss of Sharpin causes similar lesions, a conditional null mutant was created. Ubiquitously expressing cre-recombinase recapitulated the phenotype seen in spontaneous mutant mice. Limiting expression to keratinocytes (using a Krt14-cre) induced a chronic eosinophilic dermatitis, but no inflammation in other organs or lymphoid organ defects. The dermatitis was associated with a markedly increased concentration of serum IgE and IL18. Crosses with S100a4-cre resulted in milder skin lesions and moderate to severe arthritis. This conditional null mutant will enable more detailed studies on the role of SHARPIN in regulating NFkB and inflammation, while the Krt14-Sharpin-/provides a new model to study atopic dermatitis.

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“…There was increased expression of IL-4, IL-5, IL-13, and G-MCF in the skin of CPDM mice. Supernatants of cultured spleen cells of CPDM mice contained an increased amount of IL-5 and IL-13, and a decreased amount of IFN-c [18]. These systemic inflammatory cytokines may directly affect bone metabolism in CPDM mice.…”

Section: Discussionmentioning

confidence: 93%

Loss-of-function of SHARPIN causes an osteopenic phenotype in mice

Xia¹,

Liang

Ma³

et al. 2010

Endocr

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SHARPIN is a novel protein thought to interact with SHANK family and is widely expressed in multiple tissues/cells, including osteoblasts and osteoclasts. Loss-of-function of Sharpin develops the chronic proliferative dermatitis mutation (CPDM) in mice as well as a severe inflammation in other organs. The actual function of SHARPIN is poorly understood. Our aim was to determine the functional roles of SHARPIN in bone metabolism by using CPDM mice. The skeletal phenotypes were determined by peripheral quantitative computed tomography, micro-computed tomography, and quantitative real-time RT-PCR, the cellular functions of osteoblasts and osteoclasts were investigated by ex vivo cell culture. Compared to wild-type controls, CPDM mice demonstrated significantly lower total and cortical bone mineral content and bone mineral density, trabecular and cortical bone volume, and trabecular number. The mRNA expression of Runx2, osterix, type I collagen, and osteocalcin was significantly lower in the bone from CPDM mice. Osteoclasts and osteoblasts from CPDM mice were functionally defective. Our result suggests that SHARPIN plays important regulating roles in bone metabolism. These functional roles may either come from systemic chronic inflammatory or directly signaling pathway within bone cells.

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Increased expression of chemokines in the skin of chronic proliferative dermatitis mutant mice

Cited by 8 publications

References 49 publications

Chronic Proliferative Dermatitis in Sharpin Null Mice: Development of an Autoinflammatory Disease in the Absence of B and T Lymphocytes and IL4/IL13 Signaling

Chronic Proliferative Dermatitis in Sharpin Null Mice: Development of an Autoinflammatory Disease in the Absence of B and T Lymphocytes and IL4/IL13 Signaling

Keratinocyte-specific deletion of SHARPIN induces atopic dermatitis-like inflammation in mice

Loss-of-function of SHARPIN causes an osteopenic phenotype in mice

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