Chronic Proliferative Dermatitis in Mice: Neutrophil-Endothelium Interactions and the Role of Adhesion Molecules

Torres, H. I. Gallardo; Gijbels, Marion J.J.; HogenEsch, Harm; Kraal, Georg

doi:10.1159/000163970

Cited by 12 publications

(4 citation statements)

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“…(Gerlach et al, 2011; Ikeda et al, 2011; Tokunaga et al, 2011) Chronic proliferative dermatitis mutation (cpdm) mice, which are spontaneous Sharpin -deficient mutant mice, develop chronic proliferative dermatitis from 3 to 5 weeks of age. (Gallardo Torres et al, 1995; Gijbels et al, 1996; HogenEsch et al, 1993; HogenEsch et al, 1999; Seymour et al, 2006) The lifespan of this mutant mouse is shortened, and the mice show a decreased body size and a characteristic progressive dermatitis with alopecia. In this study, we found that the G186R variant affects the localization of SHARPIN proteins (Fig.…”

Section: Discussionmentioning

confidence: 99%

A rare functional variant of SHARPIN attenuates the inflammatory response and associates with increased risk of late-onset Alzheimer’s disease

Asanomi¹,

Shigemizu²,

Miyashita³

et al. 2019

Mol Med

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Background Late-onset Alzheimer’s disease (LOAD), the most common form of dementia, results from complicated interactions among multiple environmental and genetic factors. Despite recent advances in genetic analysis of LOAD, more than half of the heritability for the disease remains unclear. Although genetic studies in Caucasians found rare risk variants for LOAD with large effect sizes, these variants are hardly detectable in the Japanese population. Methods To identify rare variants possibly explaining part of the genetic architecture for LOAD in Japanese people, we performed whole-exome sequencing analyses of 202 LOAD individuals without the APOE ε4 risk allele, a major genetic factor for LOAD susceptibility. We also implemented in vitro functional analyses of the variant(s) to reveal possible functions associated with LOAD risk. Results Via step-by-step selection of whole-exome variants, we found seven candidate risk variants. We then conducted a case-control association study in a large Japanese cohort consisting of 4563 cases and 16,459 controls. We finally identified a rare nonsynonymous variant, rs572750141 (NM_030974.3:p.Gly186Arg), in SHARPIN that was potentially associated with increased risk of LOAD (corrected P = 8.05 × 10 − 5 , odds ratio = 6.1). The amino acid change in SHARPIN resulted in aberrant cellular localization of the variant protein and attenuated the activation of NF-κB, a central mediator of inflammatory and immune responses. Conclusions Our work identified a rare functional SHARPIN variant as a previously unknown genetic risk factor for LOAD. The functional alteration in SHARPIN induced by the rare coding variant is associated with an attenuated inflammatory/immune response that may promote LOAD development. Electronic supplementary material The online version of this article (10.1186/s10020-019-0090-5) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

A rare functional variant of SHARPIN attenuates the inflammatory response and associates with increased risk of late-onset Alzheimer’s disease

Asanomi¹,

Shigemizu²,

Miyashita³

et al. 2019

Mol Med

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“…Activation of the canonical NF-kB pathway, which is induced by various stimuli, including TNF-a, is attenuated in HOIL-1L-knockout (KO) and cpdm (chronic proliferative dermatitis in mice) mice (Tokunaga et al, 2009(Tokunaga et al, , 2011Gerlach et al, 2011;Ikeda et al, 2011). The latter are spontaneous mutant mice that lack SHARPIN (Gallardo Torres et al, 1995). Moreover, cpdm mice show pleomorphic phenotypes, including chronic dermatitis and immune disorders (Gallardo Torres et al, 1995;HogenEsch et al, 1999;Seymour et al, 2006Seymour et al, , 2007, indicating a crucial role for LUBAC in canonical NF-kB activation (Tokunaga et al, 2009(Tokunaga et al, , 2011Gerlach et al, 2011;Ikeda et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

“…The latter are spontaneous mutant mice that lack SHARPIN (Gallardo Torres et al, 1995). Moreover, cpdm mice show pleomorphic phenotypes, including chronic dermatitis and immune disorders (Gallardo Torres et al, 1995;HogenEsch et al, 1999;Seymour et al, 2006Seymour et al, , 2007, indicating a crucial role for LUBAC in canonical NF-kB activation (Tokunaga et al, 2009(Tokunaga et al, , 2011Gerlach et al, 2011;Ikeda et al, 2011). Moreover, deficiency of HOIL-1L provokes immunodeficiency, autoinflammatory responses, and amylopectinosis in humans (Boisson et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Defective immune responses in mice lacking LUBAC-mediated linear ubiquitination in B cells

Sasaki

Sano

Nakahara

et al. 2013

EMBO J

111

156

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The linear ubiquitin chain assembly complex (LUBAC) plays a crucial role in activating the canonical NF-jB pathway, which is important for B-cell development and function. Here, we describe a mouse model (B-HOIP Dlinear ) in which the linear polyubiquitination activity of LUBAC is specifically ablated in B cells. Canonical NF-jB and ERK activation, mediated by the tumour necrosis factor (TNF) receptor superfamily receptors CD40 and TACI, was impaired in B cells from B-HOIP Dlinear mice due to defective activation of the IKK complex; however, B-cell receptor (BCR)-mediated activation of the NF-jB and ERK pathways was unaffected. B-HOIP Dlinear mice show impaired B1-cell development and defective antibody responses to thymus-dependent and thymus-independent II antigens. Taken together, these data suggest that LUBAC-mediated linear polyubiquitination is essential for B-cell development and activation, possibly via canonical NF-jB and ERK activation induced by the TNF receptor superfamily, but not by the BCR.

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“…Although pathological changes have been well described [8], [27], this mouse model was not brought to the forefront until the mutated gene responsible was identified [6]. Little was known about the mutated gene, Sharpin , in any species [10]–[11], [28]–[29].…”

Section: Discussionmentioning

confidence: 99%

SHARPIN Negatively Associates with TRAF2-Mediated NFκB Activation

Liang

2011

PLoS ONE

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NFκB is an inducible transcriptional factor controlled by two principal signaling cascades and plays pivotal roles in diverse physiological processes including inflammation, apoptosis, oncogenesis, immunity, and development. Activation of NFκB signaling was detected in skin of SHAPRIN-deficient mice and can be diminished by an NFκB inhibitor. However, in vitro studies demonstrated that SHARPIN activates NFκB signaling by forming a linear ubiquitin chain assembly complex with RNF31 (HOIP) and RBCK1 (HOIL1). The inconsistency between in vivo and in vitro findings about SHARPIN's function on NFκB activation could be partially due to SHARPIN's potential interactions with downstream molecules of NFκB pathway. In this study, 17 anti-flag immunoprecipitated proteins, including TRAF2, were identified by mass spectrum analysis among Sharpin-Flag transfected mouse fibroblasts, B lymphocytes, and BALB/c LN stroma 12 cells suggesting their interaction with SHARPIN. Interaction between SHARPIN and TRAF2 confirmed previous yeast two hybridization reports that SHARPIN was one TRAF2's partners. Furthermore, luciferase-based NFκB reporter assays demonstrated that SHARPIN negatively associates with NFκB activation, which can be partly compensated by over-expression of TRAF2. These data suggested that other than activating NFκB signaling by forming ubiquitin ligase complex with RNF31 and RBCK1, SHARPIN may also negatively associate with NFκB activation via interactions with other NFκB members, such as TRAF2.

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Chronic Proliferative Dermatitis in Mice: Neutrophil-Endothelium Interactions and the Role of Adhesion Molecules

Cited by 12 publications

References 10 publications

A rare functional variant of SHARPIN attenuates the inflammatory response and associates with increased risk of late-onset Alzheimer’s disease

A rare functional variant of SHARPIN attenuates the inflammatory response and associates with increased risk of late-onset Alzheimer’s disease

Defective immune responses in mice lacking LUBAC-mediated linear ubiquitination in B cells

SHARPIN Negatively Associates with TRAF2-Mediated NFκB Activation

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