Mathieu-Benoit Voisin

PECAM-1: A Multi-Functional Molecule in Inflammation and Vascular Biology

Platelet endothelial cell adhesion molecule-1 (PECAM-1 or CD31) is a molecule expressed on all cells within the vascular compartment, being expressed to different degrees on most leukocyte sub-types, platelets, and on endothelial cells where its expression is largely concentrated at junctions between adjacent cells. As well as exhibiting adhesive properties, PECAM-1 is an efficient signaling molecule and is now known to have diverse roles in vascular biology including roles in angiogenesis, platelet function, and thrombosis, mechanosensing of endothelial cell response to fluid shear stress, and regulation of multiple stages of leukocyte migration through venular walls. This review will focus on some new developments with respect to the role of PECAM-1 in inflammation and vascular biology, highlighting the emerging complexities associated with the functions of this unique molecule.

Pericytes support neutrophil subendothelial cell crawling and breaching of venular walls in vivo

After transendothelial cell migration, neutrophils actively crawl along pericyte processes before exiting the venular wall via selected gaps between adjacent pericytes.

Endothelial cell activation leads to neutrophil transmigration as supported by the sequential roles of ICAM-2, JAM-A, and PECAM-1.

Leukocyte transmigration is mediated by endothelial cell (EC) junctional molecules, but the associated mechanisms remain unclear. Here we investigate how intercellular adhesion molecule-2 (ICAM-2), junctional adhesion molecule-A (JAM-A), and platelet endothelial cell adhesion molecule (PECAM-1) mediate neutrophil transmigration in a stimulus-dependent manner (eg, as induced by interleukin-1beta [IL-1beta] but not tumor necrosis factor-alpha [TNF-alpha]), and demonstrate their ability to act in sequence. Using a cell-transfer technique, transmigration responses of wild-type and TNF-alpha p55/p75 receptor-deficient leukocytes (TNFR(-/-)) through mouse cremasteric venules were quantified by fluorescence intravital microscopy. Whereas wild-type leukocytes showed a normal transmigration response to TNF-alpha in ICAM-2(-/-), JAM-A(-/-), and PECAM-1(-/-) recipient mice, TNFR(-/-) leukocytes exhibited a reduced transmigration response. Hence, when the ability of TNF-alpha to directly stimulate neutrophils is blocked, TNF-alpha-induced neutrophil transmigration is rendered dependent on ICAM-2, JAM-A, and PECAM-1, suggesting that the stimulus-dependent role of these molecules is governed by the target cell being activated. Furthermore, analysis of the site of arrest of neutrophils in inflamed tissues from ICAM-2(-/-), JAM-A(-/-), and PECAM-1(-/-) mice demonstrated that these molecules act sequentially to mediate transmigration. Collectively, the findings provide novel insights into the mechanisms of action of key molecules implicated in leukocyte transmigration.

Recent developments and complexities in neutrophil transmigration

Purpose of reviewAs the migration of neutrophils from blood to inflamed tissues is an essential component of innate immunity and a key contributing factor to the pathogenesis of inflammatory disorders, this aspect of leukocyte biology continues to be a highly dynamic field of research. This review summarizes recent findings in this area, focusing on the mechanisms that mediate neutrophil transmigration, an area where significant progress has been made. Recent findingsThe topics to be covered will include responses that are prerequisite to neutrophil migration through venular walls, such as leukocyte luminal crawling and cellular and molecular changes in leukocytes and endothelial cells (e.g. formation of protrusions) that collectively support leukocyte transendothelial cell migration. Advances in both paracellular and transcellular neutrophil migration through endothelial cells will be discussed, addressing the associated roles and regulation of expression of endothelial cell luminal and junctional adhesion molecules. Beyond the endothelium, migration through the vascular pericyte coverage and basement membrane will be reviewed. SummaryThe unquestionable role of neutrophils in the development and progression of inflammatory conditions suggests that a better understanding of the tissue-specific and stimulus-specific mechanisms that mediate this response may identify novel pathways that could be exploited for the development of more specific anti-inflammatory interventions.

Role of neutrophil elastase in LTB4‐induced neutrophil transmigration in vivo assessed with a specific inhibitor and neutrophil elastase deficient mice

The serine protease neutrophil elastase (NE) appears to regulate inflammatory responses at multiple levels but its role in leukocyte transmigration in vivo remains unclear. The present study aimed to address this issue by using both an NE inhibitor (ONO‐5046) and NE deficient (NE−/−) mice.

Both Expansion of Regulatory GR1+ CD11b+ Myeloid Cells and Anergy of T Lymphocytes Participate in Hyporesponsiveness of the Lung-Associated Immune System during Acute Toxoplasmosis

ABSTRACT Oral infection with Toxoplasma gondii leads to transient systemic hyporesponsiveness. In this report, we characterized the presence in the lungs of GR1+ CD11b+ myeloid cells that have potent nitric oxide-dependent immunoregulatory properties. We also demonstrated the interleukin 2-reversible anergy of both pulmonary CD8+ and CD4+ activated T lymphocytes with infection.

Neutrophil Transmigration: Emergence of an Adhesive Cascade within Venular Walls

Recruitment of neutrophils from the blood circulation to sites of infection or injury is a key innate immune response against invading pathogens and tissue injury. However, if inappropriately triggered, excessive and/or prolonged, this host defence response can also lead to severe pathological disorders. The migration of all leucocytes out of the vasculature is classically described by the leucocyte adhesion cascade that depicts a well-characterised sequence of cellular and molecular events within the vascular lumen. Recent findings have now illustrated that beyond the vascular lumen, the breaching of the venular wall can also involve an analogous cascade of adhesive events. For neutrophils this involves a tightly regulated and sequential series of responses within venular walls, initiating with adhesive steps that guide neutrophils through endothelial cells lining the venular wall, followed by responses that mediate and regulate their migration through the pericyte sheath and the venular basement membrane. The present review aims to provide a brief summary of novel additions to the classical adhesion cascade within the vascular lumen and then to discuss the emergence of a second adhesion cascade for neutrophils within venular walls, the latter illustrating the intricacies and complexities of neutrophil transmigration.

Junctional Adhesion Molecule-C Mediates Leukocyte Infiltration in Response to Ischemia Reperfusion Injury

Objective—Junctional adhesion molecule–C (JAM-C) is an adhesion molecule that has multiple roles in inflammation and vascular biology, but many aspects of its functions under pathological conditions are unknown. Here we investigated the role of JAM-C in leukocyte migration in response to ischemia reperfusion (I/R) injury. Methods and Results—Pretreatment of mice with soluble JAM-C (sJAM-C), used as a pharmacological blocker of JAM-C–mediated reactions, significantly suppressed leukocyte migration in models of kidney and cremaster muscle I/R injury (39 and 51% inhibition, respectively). Furthermore, in the cremaster muscle model (studied by intravital microscopy), both leukocyte adhesion and transmigration were suppressed in JAM-C–deficient mice (JAM-C−/−) and enhanced in mice overexpressing JAM-C in their endothelial cells (ECs). Analysis of JAM-C subcellular expression by immunoelectron microscopy indicated that in I/R-injured tissues, EC JAM-C was redistributed from cytoplasmic vesicles and EC junctional sites to nonjunctional plasma membranes, a response that may account for the role of JAM-C in both leukocyte adhesion and transmigration under conditions of I/R injury. Conclusions—The findings demonstrate a role for EC JAM-C in mediating leukocyte adhesion and transmigration in response to I/R injury and indicate the existence of a novel regulatory mechanism for redistribution and hence function of EC JAM-C in vivo.

Neutrophils recruited by chemoattractants in vivo induce microvascular plasma protein leakage through secretion of TNF

Adherent neutrophils responding to chemoattractants release TNF in proximity of endothelial cell junctions to mediate microvascular leakage.

Tissue localization and extracellular matrix degradation by PI, PII and PIII snake venom metalloproteinases: clues on the mechanisms of venom-induced hemorrhage

Snake venom hemorrhagic metalloproteinases (SVMPs) of the PI, PII and PIII classes were compared in terms of tissue localization and their ability to hydrolyze basement membrane components in vivo, as well as by a proteomics analysis of exudates collected in tissue injected with these enzymes. Immunohistochemical analyses of co-localization of these SVMPs with type IV collagen revealed that PII and PIII enzymes co-localized with type IV collagen in capillaries, arterioles and post-capillary venules to a higher extent than PI SVMP, which showed a more widespread distribution in the tissue. The patterns of hydrolysis by these three SVMPs of laminin, type VI collagen and nidogen in vivo greatly differ, whereas the three enzymes showed a similar pattern of degradation of type IV collagen, supporting the concept that hydrolysis of this component is critical for the destabilization of microvessel structure leading to hemorrhage. Proteomic analysis of wound exudate revealed similarities and differences between the action of the three SVMPs. Higher extent of proteolysis was observed for the PI enzyme regarding several extracellular matrix components and fibrinogen, whereas exudates from mice injected with PII and PIII SVMPs had higher amounts of some intracellular proteins. Our results provide novel clues for understanding the mechanisms by which SVMPs induce damage to the microvasculature and generate hemorrhage.