Intestinal CCL11 and eosinophilic inflammation is regulated by myeloid cell-specific RelA/p65 in mice.
Intestinal CCL11 and eosinophilic inflammation is regulated by myeloid cell-specific RelA/p65 in mice.
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DOI：
10.4049/jimmunol.1200057
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发表时间：
2013-05-01
期刊：
影响因子：
--
通讯作者：
Hogan SP
中科院分区：
文献类型：
--
作者：
Waddell A;Ahrens R;Tsai YT;Sherrill JD;Denson LA;Steinbrecher KA;Hogan SP
在炎症性肠病（IBD），特别是溃疡性结肠炎（UC）中，肠道巨噬细胞（MΦs）、嗜酸性粒细胞和嗜酸性粒细胞选择性趋化因子CCL 11与疾病的发病机制有关。MΦ是CCL 11的来源之一，据报道具有经典（NF-κ B介导）和交替激活（STAT-6介导）的混合表型。NF-κB和STAT-6通路在实验性结肠炎组织病理学中对肠道MΦ/CCL 11反应和嗜酸性粒细胞炎症的重要性尚不清楚。我们的基因阵列分析表明，儿童UC结肠活检中STAT-6和NF-κ B依赖性基因升高。葡聚糖硫酸钠（DSS）暴露诱导小鼠肠道F4/80+ CD 11 B + Ly 6 Chi（炎性）MΦ中STAT-6和NF-κB活化。DSS诱导的CCL 11表达、嗜酸性粒细胞炎症和组织病理学在RelA/p65Δmye小鼠中减弱，但在不存在STAT-6的情况下不减弱。髓系细胞中p65的缺失并不影响炎性MΦ的募集或改变凋亡，但确实减弱了纯化的F4/80+ CD 11b + Ly 6Chi炎性MΦ中脂多糖诱导的细胞因子（IL-6）产生和Ccl 11表达。分子和细胞分析揭示了DSS处理的结肠中钙卫蛋白（S100 a8/S100 a9）表达、Ccl 11表达和嗜酸性粒细胞数量之间的联系。骨髓源性MΦ的体外研究显示钙卫蛋白通过p65依赖性机制诱导CCL 11产生。我们的研究结果表明，髓样细胞特异性NF-κ B依赖性通路在实验性结肠炎中CCL 11表达和嗜酸性粒细胞炎症的维持中发挥了意想不到的作用。这些数据表明，靶向骨髓细胞和NF-κ B依赖性通路可能对IBD中嗜酸性粒细胞炎症和组织病理学的治疗有益。
In inflammatory bowel diseases (IBD), particularly ulcerative colitis (UC), intestinal macrophages (MΦs), eosinophils and the eosinophil-selective chemokine CCL11 have been associated with disease pathogenesis. MΦs, a source of CCL11, have been reported to be of a mixed classical (NF-κB-mediated) and alternatively activated (STAT-6-mediated) phenotype. The importance of NF-κB and STAT-6 pathways to the intestinal MΦ/CCL11 response and eosinophilic inflammation in the histopathology of experimental colitis is not yet understood. Our gene array analyses demonstrated elevated STAT-6- and NF-κB-dependent genes in pediatric UC colonic biopsies. Dextran sodium sulphate (DSS) exposure induced STAT-6 and NF-κB activation in mouse intestinal F4/80+CD11b+Ly6Chi (inflammatory) MΦs. DSS-induced CCL11 expression, eosinophilic inflammation and histopathology were attenuated in RelA/p65Δmye mice but not in the absence of STAT-6. Deletion of p65 in myeloid cells did not affect inflammatory MΦ recruitment or alter apoptosis, but did attenuate lipopolysaccharide-induced cytokine production (IL-6) and Ccl11 expression in purified F4/80+CD11b+Ly6Chi inflammatory MΦs. Molecular and cellular analyses revealed a link between expression of calprotectin (S100a8/S100a9), Ccl11 expression and eosinophil numbers in the DSS-treated colon. In vitro studies of bone marrow-derived MΦs showed calprotectin-induced CCL11 production via a p65-dependent mechanism. Our results indicate that myeloid cell-specific NF-κB-dependent pathways play an unexpected role in CCL11 expression and maintenance of eosinophilic inflammation in experimental colitis. These data indicate that targeting myeloid cells and NF-κB-dependent pathways may be of therapeutic benefit for the treatment of eosinophilic inflammation and histopathology in IBD.
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影响因子：
20.3
作者：
Gordy, Claire;Pua, Heather;He, You-Wen
通讯作者：
He, You-Wen
DOI：
10.1152/ajpgi.00453.2007
发表时间：
2008-03-01
影响因子：
4.5
作者：
Ghia, Jean-Eric;Galeazzi, Francesca;Collins, Stephen
通讯作者：
Collins, Stephen
影响因子：
3
作者：
Clausen, BE;Burkhardt, C;Förster, I
通讯作者：
Förster, I
影响因子：
5.3
作者：
Hertlein, E;Wang, JX;Guttridge, DC
通讯作者：
Guttridge, DC
DOI：
10.1016/s0167-4889(98)00144-x
发表时间：
1998-12-10
影响因子：
5.1
作者：
Kerkhoff, C;Klempt, M;Sorg, C
通讯作者：
Sorg, C