Lower Oligomeric Form of Surfactant Protein D in Murine Acute Lung Injury Induces M1 Subtype Macrophages Through Calreticulin/p38 MAPK Signaling Pathway.
Lower Oligomeric Form of Surfactant Protein D in Murine Acute Lung Injury Induces M1 Subtype Macrophages Through Calreticulin/p38 MAPK Signaling Pathway.
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DOI：
10.3389/fimmu.2021.687506
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发表时间：
2021
影响因子：
7.3
通讯作者：
Jiang Z
中科院分区：
文献类型：
--
作者：
Li D;Pan L;Zhang X;Jiang Z
表面活性蛋白D（SP-D）在先天性和适应性免疫应答中起重要作用。在这项研究中，我们发现，总的和去寡聚SP-D的表达显着升高，在脂多糖（LPS）诱导的急性肺损伤（ALI）小鼠。为了研究SP-D的低聚体形式在ALI发病机制中的作用，我们用ALI衍生的支气管肺泡灌洗（BAL）处理骨髓衍生的巨噬细胞（BMDM），发现ALI BAL中的SP-D主要与巨噬细胞上的钙网蛋白（CALR）结合，随后增加p38丝裂原活化蛋白激酶（MAPK）的磷酸化和白细胞介素（IL）-6的表达，肿瘤坏死因子（TNF）-α、IL-10和CD 80。然而，抗SP-D（aSP-D）和抗钙网蛋白（aCALR）预处理逆转了由ALI BAL或去寡聚化重组鼠SP-D（rSP-D）诱导的SP-D结合和巨噬细胞活化。STAT 6-/-巨噬细胞中信号转导子和转录激活子（STAT）6的缺乏导致对aCALR抑制的抗性。在ALI小鼠模型中的进一步研究表明，通过气管内（i.t.）但不是腹膜内（i. p.），给予aSP-D减轻了ALI的严重程度，伴有较低的中性粒细胞浸润和IL-1 β和IL-6的表达。此外，I.T.给予去寡聚化的rSP-D加重了ALI的严重程度，这与更多的促炎性CD 45 +Siglec-F（-）M1亚型巨噬细胞和IL-6、TNF-α、IL-1 β和IL-18的产生有关。结果表明，小鼠ALI肺中的SP-D被去寡聚化，并通过主要与巨噬细胞上的CALR结合并随后激活促炎下游信号通路参与ALI的发病机制。靶向去寡聚SP-D是治疗ALI和急性呼吸窘迫综合征（ARDS）的一种有前途的治疗策略。
Surfactant protein D (SP-D) plays an important role in innate and adaptive immune responses. In this study, we found that the expression of total and de-oligomerized SP-D was significantly elevated in mice with lipopolysaccharide (LPS)-induced acute lung injury (ALI). To investigate the role of the lower oligomeric form of SP-D in the pathogenesis of ALI, we treated bone marrow-derived macrophages (BMDMs) with ALI-derived bronchoalveolar lavage (BAL) and found that SP-D in ALI BAL predominantly bound to calreticulin (CALR) on macrophages, subsequently increasing the phosphorylation of p38 mitogen-activated protein kinase (MAPK) and expression of interleukin (IL)-6, tumor necrosis factor (TNF)-alpha, IL-10, and CD80. However, anti-SP-D (aSP-D) and anti-calreticulin (aCALR) pretreatment reversed the SP-D binding and activation of macrophages induced by ALI BAL or de-oligomerized recombinant murine SP-D (rSP-D). Lack of signal transducer and activator of transcription (STAT)6 in STAT6-/- macrophages resulted in resistance to suppression by aCALR. Further studies in an ALI mouse model showed that blockade of pulmonary SP-D by intratracheal (i.t.), but not intraperitoneal (i.p.), administration of aSP-D attenuated the severity of ALI, accompanied by lower neutrophil infiltrates and expression of IL-1beta and IL-6. Furthermore, i.t. administration of de-oligomerized rSP-D exacerbated the severity of ALI in association with more pro-inflammatory CD45+Siglec-F(-) M1 subtype macrophages and production of IL-6, TNF-alpha, IL-1beta, and IL-18. The results indicated that SP-D in the lungs of murine ALI was de-oligomerized and participated in the pathogenesis of ALI by predominantly binding to CALR on macrophages and subsequently activating the pro-inflammatory downstream signaling pathway. Targeting de-oligomerized SP-D is a promising therapeutic strategy for the treatment of ALI and acute respiratory distress syndrome (ARDS).
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影响因子：
7.3
作者：
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通讯作者：
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