IRAK-M promotes alternative macrophage activation and fibroproliferation in bleomycin-induced lung injury.
IRAK-M promotes alternative macrophage activation and fibroproliferation in bleomycin-induced lung injury.
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DOI：
10.4049/jimmunol.1402377
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发表时间：
2015-02-15
期刊：
影响因子：
--
通讯作者：
Standiford TJ
中科院分区：
文献类型：
--
作者：
Ballinger MN;Newstead MW;Zeng X;Bhan U;Mo XM;Kunkel SL;Moore BB;Flavell R;Christman JW;Standiford TJ
特发性肺纤维化(IPF)是一种以炎症和过度细胞外基质沉积为特征的破坏性肺部疾病。目前，只有有限的治疗干预措施为诊断为肺纤维化的患者提供帮助。虽然先前的研究集中在结构细胞在促进纤维化中的作用，但我们的研究评估了巨噬细胞的作用。近年来，Toll样受体(Toll-like Receptor，TLR)信号转导被认为是肺纤维化的调节因子。白介素1受体相关激酶-M(IRAK-M)是一种依赖于MyD88的TLR信号转导抑制物，它抑制有害的炎症，但可能矛盾地促进纤维化的形成。与野生型(WT)对照小鼠相比，IRAK-M缺陷小鼠(IRAK-M−/−)对博莱霉素诱导的纤维化具有保护作用，并表现出胶原沉积减少，与白介素13的产生减少有关。骨髓嵌合体实验表明，骨髓来源细胞表达IRAK-M促进了纤维化，而不是结构细胞。博莱霉素作用后，WT巨噬细胞表现出交替激活的表型，而IRAK-M−/−巨噬细胞表现出更高的经典激活巨噬细胞标志物的表达。利用体外共培养系统，从博莱霉素攻击的WT体内分离的巨噬细胞，而不是IRAK-M−/−，小鼠以IL-13依赖的方式促进肺成纤维细胞胶原和α-平滑肌肌动蛋白的表达。最后，IRAK-M在IPF患者的外周血细胞中表达上调，并与替代巨噬细胞激活的标志物相关。这些数据表明，IRAK-M的表达使肺巨噬细胞偏向于交替激活的促纤维化表型，这种表型促进了胶原的产生，导致了实验性肺纤维化的进展。
Idiopathic pulmonary fibrosis (IPF) is a devastating lung disease characterized by inflammation and the development of excessive extracellular matrix deposition. Currently, there are only limited therapeutic intervenes to offer patients diagnosed with pulmonary fibrosis. While previous studies focused on structural cells in promoting fibrosis, our study assessed the contribution of macrophages. Recently, toll-like receptor (TLR) signaling has been identified as a regulator of pulmonary fibrosis. Interleukin-1 receptor-associated kinase-M (IRAK-M), a MyD88-dependent inhibitor of TLR signaling, suppresses deleterious inflammation, but may paradoxically promote fibrogenesis. Mice deficient in IRAK-M (IRAK-M−/−) were protected against bleomycin-induced fibrosis and displayed diminished collagen deposition in association with reduced production of interleukin (IL)-13 compared to wild type (WT) control mice. Bone marrow (BM) chimera experiments indicated that IRAK-M expression by BM derived cells, rather than structural cells, promoted fibrosis. After bleomycin, WT macrophages displayed an alternatively activated phenotype, whereas IRAK-M−/− macrophages displayed higher expression of classically activated macrophage markers. Using an in vitro co-culture system, macrophages isolated from in vivo bleomycin-challenged WT, but not IRAK-M−/−, mice promoted increased collagen and α-smooth muscle actin expression from lung fibroblasts in an IL-13-dependent fashion. Finally, IRAK-M expression is upregulated in peripheral blood cells from IPF patients and correlated with markers of alternative macrophage activation. These data indicate expression of IRAK-M skews lung macrophages towards an alternatively activated profibrotic phenotype, which promotes collagen production leading to the progression of experimental pulmonary fibrosis.
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影响因子：
6
作者：
Fujita, Emiko;Shimizu, Akira;Fukuda, Yuh
通讯作者：
Fukuda, Yuh
影响因子：
13.6
作者：
Lech, Maciej;Groebmayr, Regina;Anders, Hans-Joachim
通讯作者：
Anders, Hans-Joachim
DOI：
10.1084/jem.194.6.809
发表时间：
2001-09-17
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Lee CG;Homer RJ;Zhu Z;Lanone S;Wang X;Koteliansky V;Shipley JM;Gotwals P;Noble P;Chen Q;Senior RM;Elias JA
通讯作者：
Elias JA
影响因子：
1.7
作者：
Hubbard, Leah L. N.;Ballinger, Megan N.;Moore, Bethany B.
通讯作者：
Moore, Bethany B.
DOI：
10.1084/jem.20121964
发表时间：
2013-03-11
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Molofsky AB;Nussbaum JC;Liang HE;Van Dyken SJ;Cheng LE;Mohapatra A;Chawla A;Locksley RM
通讯作者：
Locksley RM