Mac-1 Regulates IL-13 Activity in Macrophages by Directly Interacting with IL-13Rα1

Cao, Chunzhang; Zhao, Juanjuan; Doughty, Emily; Migliorini, Mary; Strickland, Dudley K.; Kann, Maricel G.; Zhang, Li

doi:10.1074/jbc.m115.645796

Cited by 9 publications

(9 citation statements)

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“…Preparations of the soluble form of LRP1 (sLRP1) and full-length Mac-1 were based on our published methods [ 10 , 53 ]. The latent PDGF-CC is incubated with 100 nM tPA in 100 µl of DMEM in a 96-well plate, with the addition of 65 nM purified Mac-1, 10 nM sLRP1 or both Mac-1 and sLRP1 at 37 °C for 90 min.…”

Section: Methodsmentioning

confidence: 99%

Microglial-mediated PDGF-CC activation increases cerebrovascular permeability during ischemic stroke

Cao

Fredriksson

et al. 2017

Acta Neuropathol

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Treatment of acute ischemic stroke with the thrombolytic tissue plasminogen activator (tPA) can significantly improve neurological outcomes; however, thrombolytic therapy is associated with an increased risk of intra-cerebral hemorrhage (ICH). Previously, we demonstrated that during stroke tPA acting on the parenchymal side of the neurovascular unit (NVU) can increase blood–brain barrier (BBB) permeability and ICH through activation of latent platelet-derived growth factor-CC (PDGF-CC) and signaling by the PDGF receptor-α (PDGFRα). However, in vitro, activation of PDGF-CC by tPA is very inefficient and the mechanism of PDGF-CC activation in the NVU is not known. Here, we show that the integrin Mac-1, expressed on brain microglia/macrophages (denoted microglia throughout), acts together with the endocytic receptor LRP1 in the NVU to promote tPA-mediated activation of PDGF-CC. Mac-1-deficient mice (Mac-1−/−) are protected from tPA-induced BBB permeability but not from permeability induced by intracerebroventricular injection of active PDGF-CC. Immunofluorescence analysis demonstrates that Mac-1, LRP1, and the PDGFRα all localize to the NVU of arterioles, and following middle cerebral artery occlusion (MCAO) Mac-1−/− mice show significantly less PDGFRα phosphorylation, BBB permeability, and infarct volume compared to wild-type mice. Bone-marrow transplantation studies indicate that resident CD11b+ cells, but not bone-marrow-derived leukocytes, mediate the early activation of PDGF-CC by tPA after MCAO. Finally, using a model of thrombotic stroke with late thrombolysis, we show that wild-type mice have an increased incidence of spontaneous ICH following thrombolysis with tPA 5 h after MCAO, whereas Mac-1−/− mice are resistant to the development of ICH even with late tPA treatment. Together, these results indicate that Mac-1 and LRP1 act as co-factors for the activation of PDGF-CC by tPA in the NVU, and suggest a novel mechanism for tightly regulating PDGFRα signaling in the NVU and controlling BBB permeability.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-017-1749-z) contains supplementary material, which is available to authorized users.

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Section: Methodsmentioning

confidence: 99%

Microglial-mediated PDGF-CC activation increases cerebrovascular permeability during ischemic stroke

Cao

Fredriksson

et al. 2017

Acta Neuropathol

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“…Protein-complexes with increased activity after cis-ligation with CR3 include FCγRIII ( 58 , 59 ), uPAR ( 60 ), tPA ( 61 ), and SLAMF7 ( 62 ). Negative regulation upon cis-ligation was reported for ICAM-1 ( 13 ), IL-13Rα1 ( 63 , 64 ), FcγRIIa ( 65 ), and CD22 ( 66 ).…”

Section: Cr3: the Master Of Ligand Versatilitymentioning

confidence: 96%

“…Ligand binding to the receptor triggers the expression of pro-inflammatory genes such as 15-LO and CD36. CR3 colocalizes with and binds the IL-13Rα1 chain via cis-ligation as a negative-feedback mechanism, thereby reducing the formation of foam cells ( 63 , 64 ). Potential interaction areas were identified within the W5 blade of the β-propeller, the α M I domain, and the CD11b leg from a co-evolution analysis of CR3 and IL-13Rα1 ( 63 ).…”

Section: Cr3 Modulating Leukocyte Functionmentioning

confidence: 99%

The Promiscuous Profile of Complement Receptor 3 in Ligand Binding, Immune Modulation, and Pathophysiology

2021

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The β2-integrin receptor family has a broad spectrum of physiological functions ranging from leukocyte adhesion, cell migration, activation, and communication to the phagocytic uptake of cells and particles. Among the members of this family, complement receptor 3 (CR3; CD11b/CD18, Mac-1, αMβ2) is particularly promiscuous in its functional profile and ligand selectivity. There are close to 100 reported structurally unrelated ligands for CR3, and while many ligands appear to cluster at the αMI domain, molecular details about binding modes remain largely elusive. The versatility of CR3 is reflected in its functional portfolio, which includes prominent roles in the removal of invaders and cell debris, induction of tolerance and synaptic pruning, and involvement in the pathogenesis of numerous autoimmune and chronic inflammatory pathologies. While CR3 is an interesting therapeutic target for immune modulation due to these known pathophysiological associations, drug development efforts are limited by concerns of potential interference with host defense functions and, most importantly, an insufficient molecular understanding of the interplay between ligand binding and functional impact. Here, we provide a systematic summary of the various interaction partners of CR3 with a focus on binding mechanisms and functional implications. We also discuss the roles of CR3 as an immune receptor in health and disease, as an activation marker in research and diagnostics, and as a therapeutic target.

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“…In this regard, circulating leukocytes of patients with sarcoidosis express higher concentrations of CD11b and CD18 (12), and the CD11b/CD18 heterodimer (Mac-1) promotes macrophage aggregation (26) and is incriminated in the context of granulomatous infections (27). Mac-1 is further shown to promote IL-13-mediated M2 macrophage polarization (28). Thus, we posit that CD11b and CD18, which are highly expressed in the in vitro sarcoidosis granuloma model (3.1-and 2.5-fold in sarcoidosis compared with controls [P , 0.05], respectively) and in diseased sarcoidosis lymph nodes (3.1-and 3.9-fold in sarcoidosis relative to controls [P , 0.05], respectively), contribute to early M2 polarization and to immune cell aggregation in the context of sarcoidosis.…”

Section: Molecular Mechanisms Of Macrophage Aggregation In Sarcoidosismentioning

confidence: 99%

IL-13–regulated Macrophage Polarization during Granuloma Formation in anIn VitroHuman Sarcoidosis Model

Locke

Crouser

White

et al. 2019

Am J Respir Cell Mol Biol

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The mechanisms underlying abnormal granuloma formation in patients with sarcoidosis are complex and remain poorly understood. A novel in vitro human granuloma model was used to determine the molecular mechanisms of granuloma-genesis in patients with sarcoidosis in response to putative disease-causing mycobacterial antigens. Peripheral blood mononuclear cells (PBMCs) from patients with active sarcoidosis and from normal, disease-free controls were incubated for 7 days with purified protein derivative (PPD)-coated polystyrene beads. Molecular responses were analyzed, as reflected by differential expression (DE) of genes, extracellular cytokine patterns, and cell surface receptor expression. Unbiased systems biology approaches were used to identify signaling pathways engaged during granuloma formation. Model findings were compared to human lung and mediastinal lymph node gene expression profiles. Compared to identically treated PBMCs of controls (n = 5), PPD-treated sarcoidosis PBMCs (n = 6) were distinguished by the formation of cellular aggregates resembling granulomas. Pathway Analysis of DE gene patterns identified molecular pathways that are primarily regulated by IL-13, which promotes alternatively-activated (M2) macrophage polarization. M2 polarization was further demonstrated by immunohistochemistry performed on the in vitro sarcoidosis granuloma-like structures. IL-13-regulated gene pathways were confirmed in human sarcoidosis lung and mediastinal lymph node tissues. The in vitro human sarcoidosis granuloma model provides novel insights into early granuloma formation, particularly IL-13 regulation of molecular networks that regulate M2 macrophage polarization. M2 macrophages are predisposed to aggregation and multinucleated giant cell formation, which are characteristic features of sarcoidosis granulomas.

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Mac-1 Regulates IL-13 Activity in Macrophages by Directly Interacting with IL-13Rα1

Cited by 9 publications

References 50 publications

Microglial-mediated PDGF-CC activation increases cerebrovascular permeability during ischemic stroke

Microglial-mediated PDGF-CC activation increases cerebrovascular permeability during ischemic stroke

The Promiscuous Profile of Complement Receptor 3 in Ligand Binding, Immune Modulation, and Pathophysiology

IL-13–regulated Macrophage Polarization during Granuloma Formation in anIn VitroHuman Sarcoidosis Model

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