Pub Date : 2020-05-01DOI: 10.1164/ajrccm-conference.2020.201.1_meetingabstracts.a7704
R. Scheraga, Susamma Abraham, L. Grove, B. Southern, J. Crish, J. Hasday, M. Olman
Mechanical cell-matrix interactions can drive the innate immune responses to infection, however the molecular underpinnings of these responses remain elusive. We have discovered that the biophysical properties of the matrix in the range of injured fibrotic lung (≥ 25 kPa) conditions the macrophage response to LPS and infection respectively through the mechanosensitive cation channel, TRPV4 in vitro and in vivo. Studies suggest that LPS-induced macrophage activation is controlled in part by the MAPK pathway (i.e. p38, ERK, JNK). Thus, we investigated if TRPV4 plays a role in the macrophage activation response after LPS through alteration of the MAPK pathway. TRPV4 KO mice exhibited reduced lung bacterial clearance by macrophages (6-fold, p=0.012) after intratracheal P. aeruginosa administration and increased lung injury as measured by inflammatory cell infiltration (≥80±3%, p<0.05), vascular permeability (BAL total protein ≥63±6%, p<0.05), and pro-inflammatory cytokine secretion in BALF (IL-6, CCL2, CXCL1 ≥71±4%, p<0.05). LPS-induced p38 activation was decreased (69%, p<0.05) while JNK activation was increased (2-fold, p<0.05) in a stiffness-dependent manner with no change in ERK activation in TRPV4 KO BMDMs. Inhibition of p38 (SB203580, BIRB796) decreased phagocytosis whereas inhibition of JNK (SP600125) decreased cytokine secretion (IL-6, CCL2, and CXCL1) after LPS (2 fold, p<0.05). DUSP1/MKP1 (MAPK phosphatase) protein was reduced by 3-fold in TRPV4 KO and inhibition of DUSP1 decreased phagocytosis and selectively increased activation of JNK. These data are the first to demonstrate new roles for macrophage TRPV4 in regulating innate immunity in a mechanosensitive manner, through MAPK activation switching.
机械细胞-基质相互作用可以驱动对感染的先天免疫反应，然而这些反应的分子基础仍然难以捉摸。我们发现，在损伤的纤维化肺(≥25 kPa)范围内，基质的生物物理性质在体外和体内分别通过机械敏感阳离子通道TRPV4调节巨噬细胞对LPS和感染的反应。研究表明，lps诱导的巨噬细胞活化部分受MAPK通路(即p38、ERK、JNK)控制。因此，我们研究了TRPV4是否通过改变MAPK通路在LPS后巨噬细胞激活反应中发挥作用。TRPV4 KO小鼠经气管内给予铜绿假单胞菌后，肺巨噬细胞清除率降低(6倍，p=0.012)，炎症细胞浸润(≥80±3%，p<0.05)、血管通透性(BAL总蛋白≥63±6%，p<0.05)、促炎细胞因子BALF分泌(IL-6、CCL2、CXCL1≥71±4%，p<0.05)均增加肺损伤。lps诱导的p38激活降低(69%，p<0.05)， JNK激活增加(2倍，p<0.05)，以刚度依赖的方式，TRPV4 KO BMDMs中ERK激活没有变化。抑制p38 (SB203580、BIRB796)可降低吞噬能力，抑制JNK (SP600125)可降低LPS后细胞因子(IL-6、CCL2、CXCL1)的分泌(2倍，p<0.05)。在TRPV4 KO中，DUSP1/MKP1 (MAPK磷酸酶)蛋白减少了3倍，DUSP1的抑制降低了吞噬作用，选择性地增加了JNK的激活。这些数据首次证明了巨噬细胞TRPV4通过MAPK激活开关以机械敏感方式调节先天免疫的新作用。
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Pub Date : 2020-05-01DOI: 10.1164/ajrccm-conference.2020.201.1_meetingabstracts.a7708
G. Rajagopalan, Sheryl L Coutermarsh-Ott, Y. Sun, B. Hu, Z. Harris, G. Stanley, J. Koff
{"title":"IL-17A and IFN-gamma Play Distinct Roles in Pulmonary and Extrapulmonary Acute Respiratory Distress Syndrome Induced by a Staphylococcal Superantigen","authors":"G. Rajagopalan, Sheryl L Coutermarsh-Ott, Y. Sun, B. Hu, Z. Harris, G. Stanley, J. Koff","doi":"10.1164/ajrccm-conference.2020.201.1_meetingabstracts.a7708","DOIUrl":"https://doi.org/10.1164/ajrccm-conference.2020.201.1_meetingabstracts.a7708","url":null,"abstract":"","PeriodicalId":351773,"journal":{"name":"D101. MECHANISTIC STUDIES OF LUNG INJURY AND REPAIR","volume":"1 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2020-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"131179516","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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