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.
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DOI：
10.1371/journal.pone.0085666
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Sundberg JP
中科院分区：
文献类型：
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作者：
Potter CS;Wang Z;Silva KA;Kennedy VE;Stearns TM;Burzenski L;Shultz LD;Hogenesch H;Sundberg JP
SHARPIN 是 NFKB 和整合素信号传导的关键调节因子。缺乏 Sharpin 的小鼠会出现一种称为慢性增殖性皮炎 (CPDM) 的表型，其特征是进行性表皮增生、角质形成细胞凋亡、皮肤和全身嗜酸性粒细胞炎症以及次级淋巴器官发育不全。将缺乏成熟 B 细胞和 T 细胞的 Rag1−/− 小鼠与 Sharpin−/− 小鼠杂交，以检查淋巴细胞在 CDPM 中的作用。尽管这些双突变小鼠的肺、肝和关节炎症有所减轻，但在缺乏功能性淋巴细胞的情况下，皮炎并未减轻，这表明淋巴细胞并不是皮肤炎症的主要驱动因素。 CPDM 中 2 型细胞因子表达增加。为了减少这方面的表型，将对 IL4 和 IL13 均无反应的 Il4ra−/− 小鼠与 Sharpin−/− 小鼠杂交。双纯合 Sharpin−/−、Il4ra−/− 小鼠出现加剧的粒细胞性皮炎、急性系统炎症以及肝坏死和矿化。通常在 CPDM 皮肤中看到的 CHI3L4 高表达在 Sharpin−/−、Il4ra−/− 双突变小鼠中被消除，表明 IL4 和 IL13 在该蛋白表达中的关键作用。尽管Il5 mRNA的表达降低并且Ccl11和Ccl24的表达完全消除，但Sharpin-/-、Il4ra-/-小鼠的皮肤嗜酸性粒细胞增多持续存在。 TSLP 和 IL33 在 Sharpin−/− 小鼠的皮肤中均增加，并且这种情况在 Sharpin−/−、Il4ra−/− 小鼠中得以维持，表明 TSLP 和 IL33 在 SHARPIN 缺陷小鼠的嗜酸性皮炎中发挥作用。这些研究表明，SHARPIN 缺陷小鼠的皮肤炎症本质上是自体炎症，独立于 B 和 T 淋巴细胞而发展，而 CPDM 中观察到的全身炎症具有强烈的淋巴细胞依赖性成分。 IL4 和 IL13 信号传导的丧失会增强皮肤和全身炎症，表明这些细胞因子通常在 SHARPIN 缺陷小鼠中发挥抗炎作用。
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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影响因子：
6.5
作者：
Leyva-Castillo, Juan Manuel;Hener, Pierre;Li, Mei
通讯作者：
Li, Mei
DOI：
10.1073/pnas.94.20.10838
发表时间：
1997-09-30
影响因子：
11.1
作者：
NobenTrauth, N;Shultz, LD;Paul, WE
通讯作者：
Paul, WE
影响因子：
64.8
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通讯作者：
Dikic, Ivan
影响因子：
32.4
作者：
Kaplan, MH;Schindler, U;Grusby, MJ
通讯作者：
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影响因子：
21.3
作者：
通讯作者：
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