Elastase Release by Transmigrating Neutrophils Deactivates Endothelial-bound SDF-1α and Attenuates Subsequent T Lymphocyte Transendothelial Migration

Rao, Ravi Mohan; Betz, Travis V.; Lamont, Deanna J.; Kim, Michael B.; Shaw, Sunil K.; Froio, Richard M.; Baleux, Françoise; Arenzana-Seisdedos, Fernando; Alon, Ronen; Luscinskas, Francis W.

doi:10.1084/jem.20040499

Cited by 62 publications

(60 citation statements)

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“…50,51 In contrast, results from a later study suggested that neutrophils may inhibit the transmigration of T cells into inflamed sites by elastase-mediated deactivation of endothelium-associated CXCL12. 52 We have recently demonstrated that monocytes regulate the transendothelial migration of neutrophils into lung grafts. 8 Future studies using intravital 2P microscopy will be helpful in defining how neutrophils regulate the trafficking of other cell populations within lungs.…”

Section: Discussionmentioning

confidence: 99%

Emergency granulopoiesis promotes neutrophil-dendritic cell encounters that prevent mouse lung allograft acceptance

Kreisel

Sugimoto²,

Zhu³

et al. 2011

Blood

105

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Section: Discussionmentioning

confidence: 99%

Emergency granulopoiesis promotes neutrophil-dendritic cell encounters that prevent mouse lung allograft acceptance

Kreisel

Sugimoto²,

Zhu³

et al. 2011

Blood

105

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“…HUVEC monolayers were stimulated with TNF-␣ (25 ng/mL for 4 hours) and then treated with SDF-1␣ (50 ng/mL; CXCL12) for 15 minutes before insertion into the flow chamber for TEM studies as previously described. 22 This step promotes T-cell TEM. 23 Human CD3 ϩ T cells (Ͼ 90% pure) were isolated by negative selection from anticoagulated whole blood of healthy volunteers as previously described.…”

Section: Human and Murine Endothelial Cell Isolation And Culture And mentioning

confidence: 99%

“…23 Human CD3 ϩ T cells (Ͼ 90% pure) were isolated by negative selection from anticoagulated whole blood of healthy volunteers as previously described. 22 Blood was drawn and handled according to protocols for protection of human subjects approved by the Brigham and Women's Hospital Institutional Review Board, and all volunteer subjects gave informed consent, in accordance with the Declaration of Helsinki. The isolation and culture of murine heart endothelial cells (MHECs) from 7-to 9-day-old pups was performed as described.…”

Section: Human and Murine Endothelial Cell Isolation And Culture And mentioning

confidence: 99%

“…22 Endothelial cells were grown to confluence on 25-mm-diameter circular glass coverslips precoated with fibronectin (5 g/ mL; BD Biosciences). HUVEC monolayers were stimulated with TNF-␣ (25 ng/mL for 4 hours) and then treated with SDF-1␣ (50 ng/mL; CXCL12) for 15 minutes before insertion into the flow chamber for TEM studies as previously described.…”

Section: Human and Murine Endothelial Cell Isolation And Culture And mentioning

confidence: 99%

“…In this model purified CD3 ϩ T cells arrest uniformly on 4 hours of TNF-␣ activated monolayers and in the presence of exogenously added apical chemokine SDF-1␣ (CXCL12), polarize, migrate to endothelial cell-cell junctions, and ultimately many transmigrate. 22 Pretreatment of HUVECs with anti-CD47 mAb B6H12 or mAb that recognize ICAM-1 (HU5/3) or class I (W6/32) did not alter T-cell accumulation on TNF-␣-activated endothelium (Figure 2A). However, anti-CD47 mAb significantly inhibited T-cell transmigration (70% Ϯ 6%; P ϭ .001; Figure 2B) and caused a 50% drop in T-cell apical migration velocity (P ϭ .001; Figure 2D).…”

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Endothelial CD47 interaction with SIRPγ is required for human T-cell transendothelial migration under shear flow conditions in vitro

Stefanidakis

Newton

Lee

et al. 2008

Blood

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Leukocyte transendothelial migration (TEM) is a critical event during inflammation. CD47 has been implicated in myeloid cell migration across endothelium and epithelium. CD47 binds to signal regulatory protein (SIRP), SIRP␣ and SIRP␥. So far, little is known about the role of endothelial CD47 in T-cell TEM in vivo or under flow conditions in vitro. Fluorescence-activated cell sorting and biochemical analysis show that CD3 ؉ T cells express SIRP␥ but not SIRP␣, and fluorescence microscopy showed that CD47 was enriched at endothelial junctions. These expression patterns suggested that CD47 plays a role in T-cell TEM through binding interactions with SIRP␥. We tested, therefore, whether CD47-SIRP␥ interactions affect T-cell transmigration using blocking mAb against CD47 or SIRP␥ in an in vitro flow model. These antibodies inhibited T-cell TEM by 70% plus or minus 6% and 82% plus or minus 1%, respectively, but had no effect on adhesion. In agreement with human mAb studies, transmigration of murine wild-type T helper type 1 cells across TNF-␣-activated murine CD47 ؊/؊ endothelium was reduced by 75% plus or minus 2% even though murine T cells appear to lack SIRP␥. Nonetheless, these findings suggest endothelial cell CD47 interacting with T-cell ligands, such as SIRP␥, play an important role in T-cell transendothelial migration. (Blood. 2008; 112:1280-1289) IntroductionRecruitment of leukocytes from the bloodstream into tissues during an inflammatory response involves a multistep adhesive and signaling cascade composed of selectin-mediated rolling and initial attachment, subsequent integrin-mediated arrest and migration on the apical surface, followed by transendothelial migration (TEM; diapedesis). 1 TEM involves multiple adhesion molecule pathways such as intracellular adhesion molecule (ICAM)-1-CD18, vascular cell adhesion molecule (VCAM)-1-VLA-4, CD47, platelet endothelial cell adhesion molecule (PECAM)-1, CD99, endothelial cell adhesion molecule (ESAM), junctional adhesion molecules (JAMs), and DNAX accessory molecule 1 [CD226]-polio virus receptor [CD155] (DNAM-1-PVR), although the cellular mechanisms controlling TEM are incompletely understood. 2 CD47 or integrin-associated protein (IAP) belongs to the immunoglobulin superfamily (IgSF) and is highly expressed in most cell types. It is a 50-kDa transmembrane protein that consists of an extracellular amino-terminal Ig domain, 5 highly hydrophobic putative membrane-spanning segments, and a short cytoplasmic tail. 3 CD47 has been shown to associate with integrins at the cell surface and signal through G-coupled proteins. 4 Important cellular ligands for CD47 are the signal regulatory proteins (SIRPs) SIRP␣ and SIRP␥. The SIRPs comprise a family of several transmembrane glycoproteins that belong to the IgSF and are present in the immune and central nervous system. 5 Each molecule contains 3 homologous extracellular Ig-like domains with distinct transmembrane and cytoplasmic domains. SIRP␣ was the first member to be identified and was detected on hematopoietic progeni...

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Synergistic Roles of Macrophages and Neutrophils in Osteoarthritis Progression

Hsueh

Zhang

Wellman

et al. 2020

Arthritis & Rheumatology

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Objective. To evaluate the role of immune cells and their effector cytokines in the pathogenesis and progression of knee osteoarthritis (OA) in matched OA synovial fluid (SF) and synovial tissue samples. Methods. Cells from matched samples of synovial tissue and SF acquired from individuals undergoing total knee replacement for OA (n = 39) were characterized for immune cell-associated surface markers and intracellular cytokine expression using polychromatic flow cytometry. Additional individuals with radiographic knee OA (Kellgren/Lawrence severity grades ≥1) who had available etarfolatide (inflammatory cell) imaging (n = 26) or baseline and 3-year data on progression of radiographic knee OA (n = 85) were also assessed. SF cytokine concentrations in all cohorts were evaluated for associations with synovial tissue and SF cell phenotypes and severity of radiographic knee OA. Results. Macrophages (predominant in the synovial tissue, 53% of total cells) and neutrophils (predominant in the SF, 26% of total cells) were the major immune cell populations identified in the OA knee joints, exhibiting expression of or association with transforming growth factor β1 (TGFβ1) and elastase, respectively, in the SF. Expression levels of TGFβ1 and elastase were significantly associated with severity of radiographic knee OA. Baseline SF concentrations of TGFβ1 and elastase along with radiographic knee OA severity scores were predictive of knee OA progression, with areas under the receiver operating characteristic curves of 0.806 (for TGFβ1), 0.810 (for elastase), and 0.846 (for both TGFβ1 and elastase combined), with greater stability of prediction when both markers were utilized. Conclusion. Our findings demonstrate the hitherto underappreciated role of neutrophils in the sterile inflammatory process and progression of OA. Two soluble mediators, SF elastase and TGFβ1, are strong predictors of knee OA progression, reflecting a synergistic role of neutrophil and macrophage populations in the pathogenesis and worsening of OA that could potentially be utilized to identify patients who may have a greater risk of more rapid disease progression.

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Elastase Release by Transmigrating Neutrophils Deactivates Endothelial-bound SDF-1α and Attenuates Subsequent T Lymphocyte Transendothelial Migration

Cited by 62 publications

References 61 publications

Emergency granulopoiesis promotes neutrophil-dendritic cell encounters that prevent mouse lung allograft acceptance

Emergency granulopoiesis promotes neutrophil-dendritic cell encounters that prevent mouse lung allograft acceptance

Endothelial CD47 interaction with SIRPγ is required for human T-cell transendothelial migration under shear flow conditions in vitro

Synergistic Roles of Macrophages and Neutrophils in Osteoarthritis Progression

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