Requirements for apoptotic cell contact in regulation of macrophage responses
Requirements for apoptotic cell contact in regulation of macrophage responses
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DOI：
10.4049/jimmunol.177.6.4047
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发表时间：
2006-09-15
影响因子：
4.4
通讯作者：
Lacy-Hulbert, Adam
中科院分区：
文献类型：
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作者：
Lucas, Mark;Stuart, Lynda M.;Lacy-Hulbert, Adam
巨噬细胞吞噬凋亡细胞的一个重要后果是抑制炎症反应，这最初是由内毒素刺激的肿瘤坏死因子-α释放测定确定的。这些效应显然部分是由受刺激的巨噬细胞亚群释放的转化生长因子-β的旁分泌效应所介导的，该亚群吞噬了凋亡细胞，从而抑制了邻近细胞。然而，刺激转化生长因子-β释放的细胞凋亡信号，以及抗炎反应所需的任何额外信号的性质仍未明确。在这项研究中，我们研究了巨噬细胞表面受体在这些反应中对凋亡细胞参与的要求。我们发现，凋亡细胞受体CD36和α(Nu)β(3)有助于小鼠巨噬细胞对凋亡细胞的吞噬，但对抗炎反应不是必需的，这表明反应和吞噬的机制是分开的。在进一步定义反应的要求时，我们确认了转化生长因子-β在抑制凋亡细胞中的重要性，并确定了对这些影响的额外控制水平。我们发现，只有当巨噬细胞首先接触到凋亡细胞时，内毒素刺激的小鼠巨噬细胞的肿瘤坏死因子-α的释放才受到抑制，因此，旁观者的巨噬细胞对吞噬的巨噬细胞释放的转化生长因子-β是不敏感的。我们的结论是，巨噬细胞群体对脂多糖驱动的肿瘤坏死因子-α释放的深刻抑制需要迄今为止尚不清楚的巨噬细胞对凋亡细胞对转化生长因子-β的反应的接触性许可。
An important consequence of macrophage engulfment of apoptotic cells is suppression of inflammatory responses, which was first defined by assay of TNF-alpha release stimulated by LPS. These effects are apparently mediated in part by paracrine effects of TGF-beta released by the subset of stimulated macrophages that ingest apoptotic cells, which suppresses neighboring cells. However, the apoptotic cell-derived signal that stimulates TGF-beta release, and the nature of any additional signals required for the antiinflammatory response remain poorly defined. In this study, we investigate the requirements for apoptotic cell engagement of macrophage surface receptors in these responses. We show that the apoptotic cell receptors CD36 and alpha(nu)beta(3) contribute to apoptotie cell phagocytosis by mouse macrophages, but are not essential for anti-inflammatory responses, suggesting that the mechanisms of response and phagocytosis are separate. In further defining requirements for response, we confirm the importance of TGF-beta in suppression by apoptotic cells, and identify an additional level of control of these effects. We show that LPS-stimulated mouse macrophage TNF-alpha release is only suppressed if macrophages have first contacted apoptotic cells, and hence, bystander macrophages are refractory to TGF-beta released by phagocytosing macrophages. We conclude that the profound suppression of LPS-driven TNF-a release by macrophage populations requires hitherto obscure contact-dependent licensing of macrophage responsiveness to TGF-beta by apoptotic cells.