Extracellular matrices regulate extravasation journey of leukocytes and inflammatory tissue fate
- Department of Stem Cell Therapy Science, Graduate School of Medicine, The University of Osaka, Japan
Figures
Figure 1
Vascular basement membrane enables endothelial mechanosensing and force-dependent junction remodeling 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 signaling is activated by laminar blood flow to trigger force-dependent actin filament remodeling 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 signaling, the basement membrane allows force generation in endothelial cells to locally remodel VE-Cadherin junctional barrier for leukocyte passage. Faint yellow stars, processes regulated by the vascular basement membrane as a collective structure. Dashed line, multi-step signaling processes.
Figure 2
Regions in the vascular basement membrane with low expression of extracellular matrices are hotspots for leukocyte passage.
(A) Laminin-511 in the vascular basement membrane signals endothelial cells to stabilize junctions via remodeling VE-Cadherin trafficking and interaction with associated intracellular stabilizing proteins. In the low expression regions, reduced local density of laminin-511, and thus the signaling to endothelial cells, loosens endothelial junctions to ease leukocyte diapedesis. (B) Typically, platelet-endothelium Ang1-Tie2 interaction keeps junctions 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. Faint yellow stars, processes regulated by specific ECM proteins from vascular basement membrane. Dashed line, multi-step signaling processes.
Figure 3
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 interactions and activities integrate to the tissue fate decision between sustained inflammation and resolution. Faint yellow stars, processes regulated by ECM proteins from vascular basement membrane or in tissue.
Figure 4
Efferocytosis exhibited by macrophages of strong S1 identity is an active driver of inflammation resolution and is regulated by specific extracellular matrices.
Macrophages sense 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 macrophages show strong S1 identity, and the efferocytic capacity is under regulation by external signaling crosstalk with cytokines and extracellular matrices.
Figure 5
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.
Appendix 1—figure 1
Updated identity definition in Macrophage Identity Kinetics Archive (MIKA).
Expansion of the archive to include more pathophysiological conditions and tissues found S1-associated stray cell states (blue shade). The original S4 identity is replaced by two surrogate identities (new S4 and S6) to S1 identity to annotate the S1-strays (asterisks). Identity vector of each updated core identity is shown. Single hashtag indicates an ambiguous population with low gene expression. Tissue-specific states are marked by yellow circles or white arrows in tissue-expanded view.
Tables
Table 1
Biological processes regulated by extracellular matrix proteins or structures at each stage along the leukocyte extravasation journey.
| Extravasation journey stage:Paracellular trans-endothelial diapedesis | ||
|---|---|---|
| ECM interaction (protein or structure) | Function | Reference |
| Vascular basement membrane/endothelial focal adhesions | Sense shear stress in blood flow to secrete PDGFs for pericyte recruitment and Ang1/Tie2-mediated junctional strengthening. | Hsieh et al., 1991; Lindblom et al., 2003; Teichert et al., 2017 |
| Sense shear stress in blood flow to endocytose VE-PTP to activate Tie2-mediated junctional strengthening. | Shirakura et al., 2023 | |
| Enable endothelial force generation pulling on VE-Cad/cateinins/actomyosin complex to expose Y731 site for dephosphorylation by SHP-2, allowing subsequent VE-Cad endocytosis and local junctional destabilization around the passaging leukocyte. | Arif et al., 2021; Wessel et al., 2014 | |
| Enable kinesin-mediated delivery of LBRC along an anchored microtubule network to endothelial junction around the passaging leukocyte for junctional destabilization. | Mamdouh et al., 2008; Mamdouh et al., 2003; Dalal et al., 2021 | |
| Laminin-511/endothelial Integrin α6β1 | Activate RhoA/ROCK to promote junctional deposition of VE-Cad to stabilize junction. | Song et al., 2017 |
| Promote p120 association to stabilize junctional VE-Cad. | Di Russo et al., 2017 | |
| Extravasation journey stage: Trans-basement membrane diapedesis | ||
| ECM interaction (protein or structure) | Function | Reference |
| Laminins / α6 integrins | Allow migration through the basement membrane barrier. | Dangerfield et al., 2002; Wang et al., 2005 |
| Vascular basement membrane/leukocyte proteases | Locally breach the basement membrane barrier. | Wang et al., 2006; Wang et al., 2005; Voisin et al., 2009 |
| Produce ECM carryovers on extravasated leukocytes. | Wang et al., 2006; Voisin et al., 2009 | |
| Laminin carryovers on neutrophils | (Unknown) | Wang et al., 2006; Voisin et al., 2009 |
| Lumican carryovers on neutrophils bound by Mac1 | Promote neutrophil migration via inducing outside-in signaling. | Lee et al., 2009 |
| Vascular basement membrane/neutrophils | Deform passaging neutrophils and activate Piezo1 to promote bactericidal activity in tissue. | Mukhopadhyay et al., 2024 |
| Collagen-IV/monocyte MMP9 | Digest locally the collagen-IV barrier to support trans-basement membrane migration of T cells. | Watanabe et al., 2018 |
| Extravasation journey stage: Immediately after extravasation | ||
| ECM interaction (protein or structure) | Function | Reference |
| Collagen/platelet GPVI | Partially activate platelets to adhere on and seal the exposed basement membrane at diapedesis sites with traffics overload. | Gros et al., 2015; Currie et al., 2022 |
| Vascular basement membrane/endothelial focal adhesions | Enable endothelial force generation stimulated by platelet Ang1-Tie2 activation to build junctional stabilizing cortical actin bundles surrounding a passaging leukocyte. | Braun et al., 2020; Braun et al., 2019 |
| Extravasation journey stage: in tissue | ||
| Function | Reference | |
| Laminin-511/monocyte integrin α6β1 | Promote monocyte differentiation to macrophage. | Li et al., 2020 |
| Collagen/MMP-8/9 and prolyl endopeptidase | Generate the matrikine PGP to secondarily chemoattract neutrophils, monocytes, and T cells. | Gaggar et al., 2008; Pfister et al., 1995; Pfister et al., 1998; Weathington et al., 2006; Watanabe et al., 2018 |
| Laminin-γ2/neutrophil elastase | Generate the matrikine FGGPNCEHGAFSCPACYNQVKI to secondarily chemoattract neutrophils. | Mydel et al., 2008 |
| Elastin/macrophage MMP-12 | Generate the matrikine VGVAPG to secondarily chemoattract monocytes. | Senior et al., 1984; Taddese et al., 2009 |
| Laminin-511/leukocyte proteases | Potentially generate fragments containing the matrikine sequence AQARSAASKVKVSMKF to secondarily chemoattract neutrophils and monocytes. | Adair-Kirk et al., 2003 |
| Versican/ADAMTS1 | Generate the matrikine (versikine) to modify macrophage cell state. | Hope et al., 2016 |
| Versikine/TLR2 (and other unknown receptors) | Increase macrophage IL-1β and IL-6 productions and decrease IL-10 production. | Hope et al., 2016 |
| Increase macrophage IL-10 production in the presence of immune complex. | Hope et al., 2016 | |
| Stimulate tumor cell production of monocyte and T cell chemokines. | Hope et al., 2016; Hope et al., 2017 | |
| Stiff tissue due to ECM build-up/leukocyte mechanosensors | Increase inflammatory cytokine production. | Saitakis et al., 2017; Fahy et al., 2019; Chakraborty et al., 2021 |
| Shift leukocyte migration from amoeboid to podosomal mode. | Sridharan et al., 2019 | |
| Modulate phagocytosis. | Sridharan et al., 2019; Adlerz et al., 2016; Mennens et al., 2017 | |
| Promote phagocyte proliferation. | Chakraborty et al., 2021 | |
| Promote phagocyte glycolysis. | Chakraborty et al., 2021 | |
| Sensitize phagocyte activation response to stimuli. | Chakraborty et al., 2021 | |
| Promote efferocytosis by Piezo1 activation. | Wang et al., 2024 | |
| α2 Laminins and type-V collagen/(unknown monocyte Receptor) | Guide monocyte differentiation to efferocytic S1 macrophage by stimulating SHP-1 to suppress STAT-5 activity. | Li et al., 2024 |
Additional files
-
Supplementary file 1
Macrophage identity kinetics of archived tissue conditions in MIKA.
Sample-wise macrophage identity proportions, tissue origin, perturbation, GEO accession, and the definition of the input cell population for single-cell RNA sequencing were indicated. Identity proportions omitting monocyte-rich S3 were also provided, useful for datasets where baseline samples showed high S3 fraction. Note that the definition and experimental preparation of the input population affect subsequent efficiency of in silico purification of macrophages and the identity composition in a sample. This results in a discrepancy of baseline identity between datasets of the same tissue (eg. GSE180420 and GSE200115). Identity kinetics is best assessed with the same definition of the input population (usually within the same dataset).
- https://cdn.elifesciences.org/articles/108284/elife-108284-supp1-v1.csv
-
Supplementary file 2
Gene correlation to each macrophage identity in MIKA.
For each tissue (baseline or perturbed), Pearson correlation coefficients of each gene to each of the macrophage identity (S1 to S6) are tabulated. Moran I coefficient shows how focused the gene expression is on UMAP. For searches of identity markers, the correlation should be considered in adjunct with gene expression (Supplementary file 3); a gene of high correlation to an identity but with low expression likely underrepresents the identity of interest.
- https://cdn.elifesciences.org/articles/108284/elife-108284-supp2-v1.csv
-
Supplementary file 3
Gene expression of each macrophage identity in MIKA.
For each core macrophage identity (S1-S6) and tissue-specific macrophage (baseline or perturbated), average gene expression is tabulated in natural logarithmic scale.
- https://cdn.elifesciences.org/articles/108284/elife-108284-supp3-v1.csv
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Extracellular matrices regulate extravasation journey of leukocytes and inflammatory tissue fate
eLife 14:RP108284.
https://doi.org/10.7554/eLife.108284.3
