Soluble SIRP-Alpha Promotes Murine Acute Lung Injury Through Suppressing Macrophage Phagocytosis.
Soluble SIRP-Alpha Promotes Murine Acute Lung Injury Through Suppressing Macrophage Phagocytosis.
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DOI：
10.3389/fimmu.2022.865579
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发表时间：
2022
影响因子：
7.3
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中科院分区：
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可溶性信号调节蛋白-α（SIRP-α）在脂多糖（LPS）诱导的急性肺损伤（ALI）小鼠支气管肺泡灌洗液（BAL）中升高。为了确定可溶性SIRP-α在ALI发病机制中的作用，我们通过腹腔内给予LPS在野生型（WT）和SIRP-α敲除（KO）小鼠中建立了小鼠ALI。结果表明，SIRP-α的缺乏显着降低了ALI的发病机制，与减轻肺部炎症，中性粒细胞浸润和促炎细胞因子在小鼠中的表达有关。此外，SIRP-α的缺乏减少了来自KO小鼠的LPS处理的骨髓源性巨噬细胞（BMDM）中促炎细胞因子的表达，伴随着巨噬细胞吞噬作用的改善。通过抗SIRP-α抗体（aSIRP）阻断ALI BAL中可溶性SIRP-α活性有效地降低了TNF-α和IL-6 mRNA转录物和蛋白的表达，提高了体外巨噬细胞吞噬作用。此外，SIRP-α的缺乏降低了含Src同源2结构域的蛋白酪氨酸磷酸酶1（SHP-1）的活化，并提高了信号转导和转录激活因子-3（STAT 3）和STAT 6的活化。酪氨酸磷酸酶抑制剂1（TPI-1）对SHP-1活性的抑制增加了STAT 3和STAT 6的活化，并改善了巨噬细胞的吞噬作用，而这一作用可被STAT 3和STAT 6抑制剂有效逆转。因此，SIRP-α通过激活SHP-1抑制巨噬细胞吞噬作用，随后抑制下游STAT 3和STAT 6信号传导。SIRP-α的缺乏可能通过增加巨噬细胞的吞噬作用和改善STAT 3和STAT 6信号转导来减轻小鼠ALI。SIRP-α有望成为治疗小鼠ALI和急性呼吸窘迫综合征（ARDS）的生物标志物和分子靶点。
Soluble signal regulatory protein-alpha (SIRP-alpha) is elevated in bronchoalveolar lavage (BAL) of mice with lipopolysaccharides (LPS)-induced acute lung injury (ALI). To define the role of soluble SIRP-alpha in the pathogenesis of ALI, we established murine ALI in wild-type (WT) and SIRP-alpha knock-out (KO) mice by intratracheal administration of LPS. The results indicated that lack of SIRP-alpha significantly reduced the pathogenesis of ALI, in association with attenuated lung inflammation, infiltration of neutrophils and expression of pro-inflammatory cytokines in mice. In addition, lack of SIRP-alpha reduced the expression of pro-inflammatory cytokines in LPS-treated bone marrow-derived macrophages (BMDMs) from KO mice, accompanied with improved macrophage phagocytosis. Blockade of soluble SIRP-alpha activity in ALI BAL by anti-SIRP-alpha antibody (aSIRP) effectively reduced the expression of TNF-alpha and IL-6 mRNA transcripts and proteins, improved macrophage phagocytosis in vitro. In addition, lack of SIRP-alpha reduced activation of Src homology 2 domain-containing protein tyrosine phosphatase 1 (SHP-1) and improved activation of signal transducer and activator of transcription-3 (STAT3) and STAT6. Suppression of SHP-1 activity by tyrosine phosphatase inhibitor 1 (TPI-1) increased activation of STAT3 and STAT6, and improved macrophage phagocytosis, that was effectively reversed by STAT3 and STAT6 inhibitors. Thereby, SIRP-alpha suppressed macrophage phagocytosis through activation of SHP-1, subsequently inhibiting downstream STAT3 and STAT6 signaling. Lack of SIRP-alpha attenuated murine ALI possibly through increasing phagocytosis, and improving STAT3 and STAT6 signaling in macrophages. SIRP-alpha would be promising biomarker and molecular target in the treatment of murine ALI and patients with acute respiratory distress syndrome (ARDS).