Figures and data
Vascular basement membrane enables endothelial mechanosensing and force-dependent junction remodelling to allow regulated leukocyte extravasation.
(A) Vascular basement membrane supports endothelial mechanosensing via focal adhesion to construct leukocyte extravasation barriers by regulating junctional strength and recruiting pericytes. Tie2 signalling is activated by laminar blood flow to trigger force-dependent actin filament remodelling to strengthen junctions. (B) After establishing firm endothelial interaction, leukocytes prefer to paracellularly transmigrate through the vascular junctional barrier near the low expression regions on the vascular basement membrane. (inset) After leukocyte signals diapedesis initiation via calcium signalling, the basement membrane allows force generation in endothelial cells to locally remodel VE-Cadherin junctional barrier for leukocyte passage. Gold spikes, processes regulated by the vascular basement membrane as a collective structure. Dashed line, multi-step signalling processes.
Regions in the vascular basement membrane with low expression of extracellular matrices are hotspots for leukocytes passage.
(A) Laminin-511 in the vascular basement membrane signals endothelial cells to stabilise junctions via remodelling VE-Cadherin trafficking and interaction with associated intracellular stabilising proteins. In the low expression regions, reduced local density of laminin-511, and thus the signalling to endothelial cells, loosens endothelial junction to ease leukocyte diapedesis. (B) Typically, platelet-endothelium Ang1-Tie2 interaction keeps junction surrounding the passaging leukocyte tight to prevent leak. However, over-usage of low expression regions exposes the basement membrane for partial platelet activation generating a plug to prevent extravasation associated vascular leak. Gold spikes, processes regulated by specific ECM proteins from vascular basement membrane. Dashed line, multi-step signalling processes.
Extracellular matrices regulate various extravasated leukocyte activities in tissue and influence fate decision of the inflamed tissue.
Biophysical and biochemical cues experienced during vascular barrier passage modify functions of extravasated leukocytes in tissue. Leukocytes also gain access to regulatory ECM components on the abluminal side of the vascular basement membrane as well as in tissue. Enzymes produced by leukocytes cleave their respective target ECM components to generate chemotactic matrikines leading to secondary leukocyte extravasation. Besides directly executing inflammatory functions, cytokines produced by leukocytes regulate ECM production by tissue stromal cells, which modulate tissue stiffness and leukocyte functions via mechanosensing. These dynamic leukocyte-ECM interaction and activities integrate to the tissue fate decision between sustained inflammation and resolution. Gold spikes, processes regulated by ECM proteins from vascular basement membrane or in tissue.
Biological processes regulated by extracellular matrix proteins or structures at each stage along the leukocyte extravasation journey.
Efferocytosis exhibited by macrophages of strong S1 identity is an active driver of inflammation resolution and is regulated by specific extracellular matrices.
Macrophage senses chemotactic materials released by apoptotic cells via an array of receptors to migrate towards and engulf them. Engulfment is mediated by receptor recognition of phosphatidylserine exposed on apoptotic cells either directly or through sandwiching adaptors. Non-apoptotic cells avoid engulfment via specific receptor complexes. Intracellular processing of endocytosed apoptotic cells activates efferocytic programs and releases anti-inflammatory mediators. Efferocytic macrophage shows strong S1 identity and the efferocytic capacity is under regulation by external signalling crosstalk with cytokines and extracellular matrices.
Extracellular matrix functional effectors are regulated by specific identities of tissue macrophage.
(A) Under the pan-tissue macrophage identity framework MIKA, tissue macrophages are segmented to six core identities (S1-S6) and tissue-specific macrophages. (B) Macrophage identities expressing ECM structural components (black diamond), regulators of matrikine production (red diamond) or regulators of tissue ECM turnovers (blue diamond) are shown.
