Surfactant proteins A and D suppress alveolar macrophage phagocytosis via interaction with SIRPα
Surfactant proteins A and D suppress alveolar macrophage phagocytosis via interaction with SIRPα
复制标题
DOI：
10.1164/rccm.200711-1661oc
复制
发表时间：
2008-07-15
影响因子：
24.7
通讯作者：
Gardai, Shyra J.
中科院分区：
文献类型：
--
作者：
Janssen, William J.;McPhillips, Kathleen A.;Gardai, Shyra J.
原理：有效去除凋亡细胞对于缓解急性肺部炎症至关重要。肺泡巨噬细胞在休息时摄取凋亡细胞的能力低于其他专职吞噬细胞，但在急性炎症期间克服了这一缺陷。表面活性蛋白（SP）-A和SP-D是巨噬细胞功能的有效调节剂，并且可以通过激活跨膜受体信号抑制调节蛋白a来抑制凋亡细胞的清除，目的：研究肺泡巨噬细胞上SP-A和SP-D与SIRP α的结合是否抑制凋亡细胞的清除。使用用SP-A、SP-D或凝集素样分子C1 q预处理的巨噬细胞评估凋亡细胞的吞噬作用。SP-A和SP-D与SIRP α的结合在体外使用阻断抗体和用活性和突变体SIRP α转染的成纤维细胞来证实。使用SHP-1缺陷小鼠、葡萄糖酸锑钠和Rho激酶抑制剂研究了下游分子SHP-1和RhoA对吞噬作用的影响。将脂多糖给予嵌合小鼠，研究SP-A和SP-D结合对炎症巨噬细胞的影响。测量和主要结果：用SP-A或SP-D预孵育巨噬细胞抑制凋亡细胞清除。通过阻断SIRP α和抑制下游分子SHP-1和RhoA来逆转表面活性剂对巨噬细胞吞噬作用的抑制。来自发炎肺的巨噬细胞比静息肺泡巨噬细胞更有效地摄取凋亡细胞。结论：SP-A和SP-D通过与SIRP α结合，对肺泡巨噬细胞吞噬功能具有抑制作用。在急性肺部炎症期间，凋亡细胞清除的缺陷被募集的单核吞噬细胞克服。
Rationale: Efficient removal of apoptotic cells is essential for the resolution of acute pulmonary inflammation. Alveolar macrophages ingest apoptotic cells less avidly than other professional phagocytes at rest but overcome this defect during acute inflammation. Surfactant protein (SP)-A and SP-D are potent modulators of macrophage function and may suppress clearance of apoptotic cells through activation of the transmembrane receptor signal inhibitory regulatory protein a, (SIRP alpha).Objectives: To investigate whether binding of SP-A and SP-D to SIRP alpha on alveolar macrophages suppresses apoptotic cell clearance.Methods: Phagocytosis of apoptotic cells was assessed using macrophages pretreated with SP-A, SP-D, or the collectin-like molecule C1q. Binding of SP-A and SP-D to SIRP alpha was confirmed in vitro using blocking antibodies and fibroblasts transfected with active and mutant SIRPa. The effects of downstream molecules SHP-1 and RhoA on phagocytosis were studied using SHP-1-deficient mice, sodium stibogluconate, and a Rho kinase inhibitor. Lipopolysaccharide was given to chimeric mice to study the effects of SP-A and SP-D binding on inflammatory macrophages.Measurements and Main Results: Preincubation of macrophages with SP-A or SP-D suppressed apoptotic cell clearance. Surfactant suppression of macrophage phagocytosis was reversed by blocking SIRP alpha and inhibiting downstream molecules SHP-1 and RhoA. Macrophages from inflamed lungs ingested apoptotic cells more efficiently than resting alveolar macrophages. Recruited mononuclear phagocytes with low levels of SP-A and SP-D mediated this effect.Conclusions: SP-A and SP-D tonically inhibit alveolar macrophage phagocytosis by binding SIRP alpha. During acute pulmonary inflammation, defects in apoptotic cell clearance are overcome by recruited mononuclear phagocytes.