CXCR4 negatively regulates keratinocyte proliferation in IL-23-mediated psoriasiform dermatitis.
CXCR4 negatively regulates keratinocyte proliferation in IL-23-mediated psoriasiform dermatitis.
复制标题
DOI：
10.1038/jid.2013.151
复制
发表时间：
2013-11
影响因子：
6.5
通讯作者：
Hwang, Sam T.
中科院分区：
文献类型：
--
作者：
Takekoshi, Tomonori;Wu, Xuesong;Mitsui, Hiroshi;Tada, Yayoi;Kao, Mandy C.;Sato, Shinichi;Dwinell, Michael B.;Hwang, Sam T.
CXCR 4由基底角质形成细胞（KCs）表达，但对其在炎症皮肤中的功能知之甚少。我们将K14-Cre和CXCR 4flox/flox（f/f）转基因小鼠杂交，导致K14表达细胞（K14-CXCR 4KO）中CXCR 4基因特异性缺失的小鼠，包括基础KC。K14-CXCR 4KO幼仔没有明显的皮肤缺陷。我们在IL-23介导的银屑病样皮炎模型中比较了K14-CXCR 4KO和CXCR 4f/f对照小鼠，并测量了皮肤水肿、组织学和免疫组织学变化。IL-23处理的K14-CXCR 4KO小鼠显示平均耳肿胀增加1.3倍，表皮厚度增加2倍，角化不全更严重。IL-23处理的WT小鼠在严重表皮增生区域显示弱CXCR 4表达，但在非增生区域显示强CXCR 4表达，表明CXCR 4可调节角质形成细胞增殖。为了验证这一假设，我们在HaCaT角质形成细胞中过表达CXCR 4，并用IL-22和/或CXCL 12处理它们。CXCL 12在体外阻断IL-22介导的HaCaT细胞增殖，并与IL-22协同上调STAT 3的关键调节因子SOCS 3。CXCR 4介导的生长抑制需要SOCS 3。在人类银屑病皮肤中，CXCR 4和SOCS 3在银屑病斑块边缘的交界区均上调。因此，CXCR 4在抑制KC增殖和减轻增殖性Th 17细胞因子的作用方面发挥了意想不到的作用。
CXCR4 is expressed by basal keratinocytes (KCs), but little is known about its function in inflamed skin. We crossed K14-Cre and CXCR4flox/flox (f/f) transgenic mice, resulting in mice with specific loss of the CXCR4 gene in K14-expressing cells (K14-CXCR4KO), including basal KCs. K14-CXCR4KO pups had no obvious skin defects. We compared K14-CXCR4KO and CXCR4f/f control mice in an IL-23-mediated psoriasisform dermatitis model and measured skin edema, histologic, and immunohistological changes. IL-23-treated K14-CXCR4KO mice showed a 1.3-fold increase in mean ear swelling, 2-fold increase in epidermal thickness, and greater parakeratosis. IL-23-treated WT mice showed weak CXCR4 expression in areas of severe epidermal hyperplasia, but strong CXCR4 expression in non-hyperplastic regions, suggesting CXCR4 may regulate keratinocyte proliferation. To test this hypothesis, we overexpressed CXCR4 in HaCaT keratinocyte cells and treated them with IL-22 and/or CXCL12. CXCL12 blocked IL-22-mediated HaCaT cell proliferation in vitro and synergized with IL-22 in upregulating SOCS3, a key regulator of STAT3. SOCS3 was required for CXCR4-mediated growth inhibition. In human psoriatic skin, both CXCR4 and SOCS3 were upregulated in the junctional region at the border of psoriatic plaques. Thus, CXCR4 plays an unexpected role in inhibiting KC proliferation and mitigating the effects of proliferative Th17 cytokines.
登录
查看更多内容
DOI：
10.1084/jem.20060244
发表时间：
2006-11-27
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Chan JR;Blumenschein W;Murphy E;Diveu C;Wiekowski M;Abbondanzo S;Lucian L;Geissler R;Brodie S;Kimball AB;Gorman DM;Smith K;de Waal Malefyt R;Kastelein RA;McClanahan TK;Bowman EP
通讯作者：
Bowman EP
影响因子：
3.7
作者：
Romanowska M;Reilly L;Palmer CN;Gustafsson MC;Foerster J
通讯作者：
Foerster J
影响因子：
5.5
作者：
Fang, Lei;Lee, Vivian C.;Hwang, Sam T.
通讯作者：
Hwang, Sam T.
DOI：
10.1084/jem.20030593
发表时间：
2003-11-03
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Murakami T;Cardones AR;Finkelstein SE;Restifo NP;Klaunberg BA;Nestle FO;Castillo SS;Dennis PA;Hwang ST
通讯作者：
Hwang ST
影响因子：
3.7
作者：
Kreis S;Philippidou D;Margue C;Rolvering C;Haan C;Dumoutier L;Renauld JC;Behrmann I
通讯作者：
Behrmann I