Lower Oligomeric Form of Surfactant Protein D in Murine Acute Lung Injury Induces M1 Subtype Macrophages Through Calreticulin/p38 MAPK Signaling Pathway
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...
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doaj-b1e983a6a65f4971af355e001e014db12021-08-16T08:48:33ZengFrontiers Media S.A.Frontiers in Immunology1664-32242021-08-011210.3389/fimmu.2021.687506687506Lower Oligomeric Form of Surfactant Protein D in Murine Acute Lung Injury Induces M1 Subtype Macrophages Through Calreticulin/p38 MAPK Signaling PathwayDandan Li0Dandan Li1Linyue Pan2Xiaoju Zhang3Zhilong Jiang4Department of Pulmonary and Critical Care Medicine, Henan Provincial People’s Hospital, People’s Hospital of Zhengzhou University, Zhengzhou, ChinaDepartment of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai, ChinaDepartment of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai, ChinaDepartment of Pulmonary and Critical Care Medicine, Henan Provincial People’s Hospital, People’s Hospital of Zhengzhou University, Zhengzhou, ChinaDepartment of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai, ChinaSurfactant 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).https://www.frontiersin.org/articles/10.3389/fimmu.2021.687506/fullacute lung injurymacrophagessurfactant protein Dcalreticulinsignal regulatory protein-alpha |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Dandan Li Dandan Li Linyue Pan Xiaoju Zhang Zhilong Jiang |
spellingShingle |
Dandan Li Dandan Li Linyue Pan Xiaoju Zhang Zhilong Jiang Lower Oligomeric Form of Surfactant Protein D in Murine Acute Lung Injury Induces M1 Subtype Macrophages Through Calreticulin/p38 MAPK Signaling Pathway Frontiers in Immunology acute lung injury macrophages surfactant protein D calreticulin signal regulatory protein-alpha |
author_facet |
Dandan Li Dandan Li Linyue Pan Xiaoju Zhang Zhilong Jiang |
author_sort |
Dandan Li |
title |
Lower Oligomeric Form of Surfactant Protein D in Murine Acute Lung Injury Induces M1 Subtype Macrophages Through Calreticulin/p38 MAPK Signaling Pathway |
title_short |
Lower Oligomeric Form of Surfactant Protein D in Murine Acute Lung Injury Induces M1 Subtype Macrophages Through Calreticulin/p38 MAPK Signaling Pathway |
title_full |
Lower Oligomeric Form of Surfactant Protein D in Murine Acute Lung Injury Induces M1 Subtype Macrophages Through Calreticulin/p38 MAPK Signaling Pathway |
title_fullStr |
Lower Oligomeric Form of Surfactant Protein D in Murine Acute Lung Injury Induces M1 Subtype Macrophages Through Calreticulin/p38 MAPK Signaling Pathway |
title_full_unstemmed |
Lower Oligomeric Form of Surfactant Protein D in Murine Acute Lung Injury Induces M1 Subtype Macrophages Through Calreticulin/p38 MAPK Signaling Pathway |
title_sort |
lower oligomeric form of surfactant protein d in murine acute lung injury induces m1 subtype macrophages through calreticulin/p38 mapk signaling pathway |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Immunology |
issn |
1664-3224 |
publishDate |
2021-08-01 |
description |
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). |
topic |
acute lung injury macrophages surfactant protein D calreticulin signal regulatory protein-alpha |
url |
https://www.frontiersin.org/articles/10.3389/fimmu.2021.687506/full |
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