Impaired phagocytosis of apoptotic cells by macrophages in chronic granulomatous disease is reversed by IFN-γ in a nitric oxide-dependent manner.
Impaired phagocytosis of apoptotic cells by macrophages in chronic granulomatous disease is reversed by IFN-γ in a nitric oxide-dependent manner.
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DOI：
10.4049/jimmunol.1001778
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发表时间：
2010-10-01
期刊：
影响因子：
--
通讯作者：
Bratton DL
中科院分区：
文献类型：
--
作者：
Fernandez-Boyanapalli R;McPhillips KA;Frasch SC;Janssen WJ;Dinauer MC;Riches DW;Henson PM;Byrne A;Bratton DL
慢性肉芽肿病（CGD）的免疫缺陷是很好的特点。不太了解的是与CGD相关的夸大的无菌炎症和自身免疫。凋亡细胞的识别和清除受损，导致其解体，可能有助于CGD炎症。我们假设，用IFN-γ引发巨噬细胞（M β）将增强CGD中凋亡细胞的受损吞噬。来自CGD（gp 91 phox −/−）和野生型小鼠的不同M β细胞群，以及从单核细胞和早幼粒细胞白血病PLB-985细胞分化的人M β细胞（有和没有gp 91 phox突变），表现出对IFN-γ引发的凋亡细胞的吞噬增强。用IFN-γ引发也与Ig调理的靶标、乳胶珠和流体相标志物的摄取增加相关，并且伴随着Rho GT3 Rac的激活。IFN-γ引发后Rac激活和吞噬作用的增强依赖于通过诱导型NO合酶和蛋白激酶G激活的NO产生。值得注意的是，响应于IFN-γ引发的TNF-α的内源性产生是诱导型NO合酶上调、NO产生、Rac活化和增强的吞噬作用所必需的。用IFN-γ处理CGD小鼠也通过信号传导途径增强了体内M β对凋亡细胞的摄取。重要的是，在急性无菌性腹膜炎期间，IFN-γ治疗减少了凋亡中性粒细胞的过度积累，并增强了CGD M β的吞噬作用。这些数据支持以下假设：除了纠正CGD中的免疫缺陷外，IFN-γ引发的M β细胞恢复了凋亡细胞的清除，从而可能有助于缓解过度的CGD炎症。
Immunodeficiency in chronic granulomatous disease (CGD) is well characterized. Less understood are exaggerated sterile inflammation and autoimmunity associated with CGD. Impaired recognition and clearance of apoptotic cells resulting in their disintegration may contribute to CGD inflammation. We hypothesized that priming of macrophages (Mϕs) with IFN-γ would enhance impaired engulfment of apoptotic cells in CGD. Diverse Mϕ populations from CGD (gp91phox−/−) and wild-type mice, as well as human Mϕs differentiated from monocytes and promyelocytic leukemia PLB-985 cells (with and without mutation of the gp91phox), demonstrated enhanced engulfment of apoptotic cells in response to IFN-γ priming. Priming with IFN-γ was also associated with increased uptake of Ig-opsonized targets, latex beads, and fluid phase markers, and it was accompanied by activation of the Rho GTPase Rac. Enhanced Rac activation and phagocytosis following IFN-γ priming were dependent on NO production via inducible NO synthase and activation of protein kinase G. Notably, endogenous production of TNF-α in response to IFN-γ priming was critically required for inducible NO synthase upregulation, NO production, Rac activation, and enhanced phagocytosis. Treatment of CGD mice with IFN-γ also enhanced uptake of apoptotic cells by Mϕ in vivo via the signaling pathway. Importantly, during acute sterile peritonitis, IFN-γ treatment reduced excess accumulation of apoptotic neutrophils and enhanced phagocytosis by CGD Mϕs. These data support the hypothesis that in addition to correcting immunodeficiency in CGD, IFN-γ priming of Mϕs restores clearance of apoptotic cells and may thereby contribute to resolution of exaggerated CGD inflammation.
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影响因子：
32.4
作者：
Hegazy, Ahmed N.;Peine, Michael;Loehning, Max
通讯作者：
Loehning, Max
影响因子：
2.9
作者：
GREEN, LC;WAGNER, DA;TANNENBAUM, SR
通讯作者：
TANNENBAUM, SR
影响因子：
56.9
作者：
KARUPIAH, G;XIE, QW;MACMICKING, JD
通讯作者：
MACMICKING, JD
影响因子：
4.4
作者：
Fadok, VA;Bratton, DL;Henson, PM
通讯作者：
Henson, PM
影响因子：
5.1
作者：
GALLIN, JI;BUESCHER, ES
通讯作者：
BUESCHER, ES