Endothelial CD99 signals through soluble adenylyl cyclase and PKA to regulate leukocyte transendothelial migration

Watson, Richard L.; Buck, Jochen; Levin, Lonny R.; Winger, Ryan C.; Wang, Jing; Arase, Hisashi; Müller, William A.

doi:10.1084/jem.20150354

Cited by 89 publications

(128 citation statements)

References 64 publications

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“…This results in chemokine and cytokine release by various cell types followed by inflammation close to the site of injury. diapedesis of monocytes, neutrophils and T-cells was established 104,105 making this junctional protein of interest in the context of unraveling the initial receptor involved in formatting of a confined actin pore during leukocyte TEM. Intracellular CD99 signaling regulating leukocyte TEM has recently been described to involve soluble adenylyl cyclase (sAC) that activates protein kinase A (PKA).…”

Section: Junctional Protein Candidatesmentioning

confidence: 99%

“…This activation occurs at the lysine-rich intracellular tail of CD99 using the A-kinase anchoring protein (AKAP) ezrin as a scaffold. 104 Involvement of ezrin in this signaling complex could connect homophilic CD99 interaction to formation of the F-actin rich pore, because ezrin belongs to the ERM family (ezrin/ radixin/moesin) of proteins that link actin filaments to the plasma membrane. Moreover, CD99 functions at a later stage during the diapedesis step, i.e., when the leukocyte has worked its way into the junction already.…”

Section: Junctional Protein Candidatesmentioning

confidence: 99%

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Leukocyte transendothelial migration: A local affair

2016

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Inflammation is part of the complex biological response of body tissues to harmful stimuli, such as pathogens. It serves as a protective response that involves leukocytes, blood vessels and molecular mediators with the purpose to eliminate the initial cause of cell injury and to initiate tissue repair. Inflammation is tightly regulated by the body and is associated with transient crossing of leukocytes through the blood vessel wall, a process called transendothelial migration (TEM) or diapedesis. TEM is a close collaboration between leukocytes on one hand and the endothelium on the other. Limiting vascular leakage during TEM but also when the leukocyte has crossed the endothelium is essential for maintaining vascular homeostasis. Although many details have been uncovered during the recent years, the molecular mechanisms from the vascular part that drive TEM still shows significant gaps in our understanding. This review will focus on the local signals that are induced in the endothelium that regulate leukocyte TEM and simultaneous preservation of endothelial barrier function.

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Section: Junctional Protein Candidatesmentioning

confidence: 99%

Section: Junctional Protein Candidatesmentioning

confidence: 99%

Leukocyte transendothelial migration: A local affair

2016

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“…The findings reported here give us new insights into the mechanisms leading to expression of CD1a on human DCs and the critical role of CD99 transmembrane molecule in this expression. We describe here a new function for the CD99 molecule aside from its role in the regulation of the expression of MHC class I [32]. Here we report that CD99 is involved through a distinct mechanism in the regulation of CD1a through its transcription.…”

Section: Discussionmentioning

confidence: 82%

Section: Introductionmentioning

confidence: 99%

“…The mRNA of CD99 is expressed as two isoforms, a long form of 185 amino acids (CD99LF) and a short form of 161 amino acids (CD99SF) obtained by alternative splicing of the cytoplasmic region [27]. Aside from its role in the regulation of adherence, cell death and transendothelial migration [28][29][30][31][32] we previously showed that CD99 plays an active role in the transport of MHC class I molecules [33].Here we studied the role of CD99 in the expression of CD1a during generation of human CD14+ -derived iDCs in vitro. We found that the expression of CD1a was linked to the isomorphism of CD99, in particular through its long form, as a consequence of its effect on the phosphorylation of ATF-2 transcription factor.…”

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confidence: 99%

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CD99 isoforms regulate CD1a expression in human monocyte‐derived DCs through ATF‐2/CREB‐1 phosphorylation

et al. 2016

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CD1a expression is considered one of the major characteristics qualifying in vitro human dendritic cells (DCs) during their generation process. Here, we report that CD1A transcription is regulated by a mechanism involving the long and short isoforms of CD99. Using a lentiviral construct encoding for a CD99 short hairpin RNA, we were able to inhibit CD99 expression in human primary DCs. In such cells, CD1a membrane expression increased and CD1A transcripts were much higher in abundance compared to cells expressing CD99 long form (CD99LF). We also show that CD1A transcription is accompanied by a switch in expression from CD99LF to expression at comparable levels of both CD99 isoforms during immature DCs generation in vitro. We demonstrate that CD99LF maintains a lower level of CD1A transcription by up-regulating the phosphorylated form of the ATF-2 transcription factor and that CD99 short form (SF) is required to counteract this regulatory mechanism. Elucidation of the molecular mechanisms related to CD99 alternative splicing will be very helpful to better understand the transcriptional regulatory mechanism of CD1a molecules during DCs differentiation and its involvement in the immune response.Keywords: alternative splicing-ATF2-CREB1 r CD99 r Dendritic cells r Nonclassical MHC Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionPresentation of foreign antigens in the form of proteins or lipids solicits specialized molecular complexes carried by dendritic cells (DCs). The molecules of the classical and nonclassical major Correspondence: Dr. Ghislaine Bernard e-mail: bernardg@unice.fr histocompatibility complex (MHC) class I present antigens to T cells and these two families of molecules have very similar structures [1][2][3].Among the nonclassical MHC molecules is the CD1 family of molecules that assures the presentation of lipid and glycolipid † Deceased C 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2016. 46: 1460-1471 Immunomodulation 1461 antigens [4,5]. This family consists of five genes, including CD1A, B, C, D and E. The first four give rise to cell surface proteins CD1a, CD1b, CD1c, CD1d that are able to present the antigens, while the gene CD1E codes for the cytoplasmic protein CD1e [6][7][8]. CD1a is expressed on the membranes of thymocytes, dermal DCs and Langerhans cells, and allows distinction between subpopulations of DCs. No such equivalent has been reported in mice [8].CD1a is expressed during generation of DCs derived from monocytes when cultured in the presence of GMCSF and IL4 in vitro [9]. Two subpopulations of immature DCs (iDCs), i.e. CD1a high and CD1a low DCs, are produced in these conditions [10,11]. In addition to their phenotypic differences, these cells show functional differences, in particular in terms of secretion of cytokines. In contrast to CD1a high DCs, CD1a low DCs produce low amounts of IL12 but produce high amounts of IL10. This profile of cytokines impacts on the f...

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Immunological Adhesion and Homing Molecules

Baldanzi

2019

Encyclopedia of Life Sciences

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The immunosurveillance function of leukocytes requires a strictly controlled trafficking between lymphoid and nonlymphoid tissues. Thus, white blood cells are continuously scanning the body for sign of infection or damage with lineage‐specific pathways. Triggered by chemokines and other danger signals, those movements require selective interactions mediated by adhesion and homing molecules expressed by immune and endothelial cells. Typically, the transendothelial migration is initiated by specific interactions between selectins and glycosylated proteins, which allow the initial tethering and rolling of leukocytes on endothelial cells. In the presence of chemokines, rolling is followed by firm arrest mediated by active integrins binding to immunoglobulin superfamily ligands and culminates with extravasation. The expression pattern and structural features of those adhesion molecules dictated the cell‐specific homing governing the immune response. Key Concepts Leukocytes exit from circulation to home at secondary lymphoid organs and peripheral tissues. Essential steps of extravasation are tethering, rolling, firm adhesion and diapedesis. The typical homing cascade sees selectins binding to glycoproteins during rolling, followed by chemokine mediated integrin activation promoting firm adhesion. Endothelial cells have an active role in lymphocyte recruitment, presentation of chemokines and transendothelial transport of leukocytes. Homing molecules are controlled by the engagement by ligands and by the shear force applied to them.

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Endothelial CD99 signals through soluble adenylyl cyclase and PKA to regulate leukocyte transendothelial migration

Cited by 89 publications

References 64 publications

Leukocyte transendothelial migration: A local affair

Leukocyte transendothelial migration: A local affair

CD99 isoforms regulate CD1a expression in human monocyte‐derived DCs through ATF‐2/CREB‐1 phosphorylation

Immunological Adhesion and Homing Molecules

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