The generation of macrophages with anti-inflammatory activity in the absence of STAT6 signaling
The generation of macrophages with anti-inflammatory activity in the absence of STAT6 signaling
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DOI：
10.1189/jlb.2a1114-560r
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发表时间：
2015-09-01
影响因子：
5.5
通讯作者：
Mosser, David M.
中科院分区：
文献类型：
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作者：
Fleming, Bryan D.;Chandrasekaran, Prabha;Mosser, David M.
巨噬细胞很容易改变其表型以响应外源刺激。在这项工作中，巨噬细胞在各种实验条件下受到刺激，表型改变与基因表达的变化相关。我们鉴定了 3 个具有免疫调节活性的转录相关巨噬细胞群。它们是通过在 3 种不同的“重编程”信号存在下用 TLR 配体刺激细胞而产生的：高密度 IC、PGE(2) 或 Ado。所有这 3 个细胞群都产生高水平的 IL-10 以及生长因子和血管生成因子的转录物。它们还分泌降低水平的炎症细胞因子 IL-1β、IL-6 和 IL-12。所有 3 种巨噬细胞表型都可以部分拯救小鼠免于致死性内毒素血症，因此，我们认为每种巨噬细胞表型都具有抗炎活性。这种调节先天免疫反应的能力在 STAT6 缺陷小鼠的巨噬细胞中也同样有效。 STAT6的缺乏并不影响巨噬细胞相互改变细胞因子产生或将小鼠从致命性内毒素血症中拯救出来的能力。此外，用 IL-4 处理巨噬细胞未能诱导类似的表型或转录改变。这项工作表明，有多种方法可以产生具有免疫调节活性的巨噬细胞。这些抗炎巨噬细胞在转录和功能上彼此相关，并且与用 IL-4 处理的巨噬细胞截然不同。
Macrophages readily change their phenotype in response to exogenous stimuli. In this work, macrophages were stimulated under a variety of experimental conditions, and phenotypic alterations were correlated with changes in gene expression. We identified 3 transcriptionally related populations of macrophages with immunoregulatory activity. They were generated by stimulating cells with TLR ligands in the presence of 3 different "reprogramming" signals: high-density ICs, PGE(2), or Ado. All 3 of these cell populations produced high levels of transcripts for IL-10 and growth and angiogenic factors. They also secreted reduced levels of inflammatory cytokines IL-1 beta, IL-6, and IL-12. All 3 macrophage phenotypes could partially rescue mice from lethal endotoxemia, and therefore, we consider each to have anti-inflammatory activity. This ability to regulate innate-immune responses occurred equally well in macrophages from STAT6-deficient mice. The lack of STAT6 did not affect the ability of macrophages to change cytokine production reciprocally or to rescue mice from lethal endotoxemia. Furthermore, treatment of macrophages with IL-4 failed to induce similar phenotypic or transcriptional alterations. This work demonstrates that there are multiple ways to generate macrophages with immunoregulatory activity. These anti-inflammatory macrophages are transcriptionally and functionally related to each other and are quite distinct from macrophages treated with IL-4.