An AXL/LRP-1/RANBP9 complex mediates DC efferocytosis and antigen cross-presentation in vivo

Subramanian, Manikandan; Hayes, Crystal D.; Thome, Joseph J.C.; Thorp, Edward B.; Matsushima, Glenn K.; Herz, Joachim; Farber, Donna L.; Liu, Kang; Lakshmana, Madepalli K.; Tabas, Ira

doi:10.1172/jci72051

Cited by 103 publications

(106 citation statements)

References 55 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Although we previously demonstrated that TNF receptor-1 (TNFR1) is increased in LRP1-deficient fibroblasts (12,42), TNFR1 regulation does not provide a straightforward explanation for the activity of LRP1 ligands. LRP1 demonstrates other important activities in macrophages that may be critical in tissue injury and the inflammatory response, including its function in phagocytosis of large particles (12), efferocytosis (15,43), and in regulating transforming growth factor-β (44). LRP1 also is involved in antigen presentation in support of adaptive immunity (45,46).…”

Section: Discussionmentioning

confidence: 99%

LDL receptor-related protein-1 regulates NFκB and microRNA-155 in macrophages to control the inflammatory response

Mantuano

Brifault

Lam

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

112

160

View full text Add to dashboard Cite

LDL receptor-related protein-1 (LRP1) is an endocytic and cellsignaling receptor. In mice in which LRP1 is deleted in myeloid cells, the response to lipopolysaccharide (LPS) was greatly exacerbated. LRP1 deletion in macrophages in vitro, under the control of tamoxifen-activated Cre-ER T fusion protein, robustly increased expression of proinflammatory cytokines and chemokines. In LRP1-expressing macrophages, proinflammatory mediator expression was regulated by LRP1 ligands in a ligand-specific manner. The LRP1 agonists, α 2 -macroglobulin and tissue-type plasminogen activator, attenuated expression of inflammatory mediators, even in the presence of LPS. The antagonists, receptor-associated protein (RAP) and lactoferrin (LF), and LRP1-specific antibody had the entirely opposite effect, promoting inflammatory mediator expression and mimicking LRP1 deletion. NFκB was rapidly activated in response to RAP and LF and responsible for the initial increase in expression of proinflammatory mediators. RAP and LF also significantly increased expression of microRNA-155 (miR-155) after a lag phase of about 4 h. miR-155 expression reflected, at least in part, activation of secondary cell-signaling pathways downstream of TNFα. Although miR-155 was not involved in the initial induction of cytokine expression in response to LRP1 antagonists, miR-155 was essential for sustaining the proinflammatory response. We conclude that LRP1, NFκB, and miR-155 function as members of a previously unidentified system that has the potential to inhibit or sustain inflammation, depending on the continuum of LRP1 ligands present in the macrophage microenvironment.LDL receptor-related protein-1 | tissue-type plasminogen activator | lipopolysaccharide | NFκB | microRNA-155

show abstract

Section: Discussionmentioning

confidence: 99%

LDL receptor-related protein-1 regulates NFκB and microRNA-155 in macrophages to control the inflammatory response

Mantuano

Brifault

Lam

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

112

160

View full text Add to dashboard Cite

show abstract

“…Axl-mediated phagocytosis has previously been described to occur mainly in dendritic cells (25,61) and specifically under pro-inflammatory conditions (62), whereas Mer in both circulating and tissue-resident macrophages was suggested to contribute to homeostatic apoptotic clearance under tolerogenic settings. As the PMPs represent a large part of circulating MPs even under basal conditions, their phagocytic uptake could be expected to occur in a constantly ongoing manner resembling homeostatic Mer-dependent phagocytosis.…”

Section: Discussionmentioning

confidence: 99%

The Gas6-Axl Protein Interaction Mediates Endothelial Uptake of Platelet Microparticles

Happonen

Tran

Mörgelin

et al. 2016

Journal of Biological Chemistry

View full text Add to dashboard Cite

Upon activation, platelets release plasma membrane-derived microparticles (PMPs) exposing phosphatidylserine on their surface. The functions and clearance mechanism of these microparticles are incompletely understood. As they are pro-coagulant and potentially pro-inflammatory, rapid clearance from the circulation is essential for prevention of thrombotic diseases. The tyrosine kinase receptors Tyro3, Axl, and Mer (TAMs) and their ligands protein S and Gas6 are involved in the uptake of phosphatidylserine-exposing apoptotic cells in macrophages and dendritic cells. Both TAMs and their ligands are expressed in the vasculature, the functional significance of which is poorly understood. In this study, we investigated how vascular TAMs and their ligands may mediate endothelial uptake of PMPs. PMPs, generated from purified human platelets, were isolated by ultracentrifugation and labeled with biotin or PKH67. The uptake of labeled microparticles in the presence of protein S and Gas6 in human aortic endothelial cells and human umbilical vein endothelial cells was monitored by flow cytometry, Western blotting, and confocal/electron microscopy. We found that both endothelial cell types can phagocytose PMPs, and by using TAM-blocking antibodies or siRNA knockdown of individual TAMs, we show that the uptake is mediated by endothelial Axl and Gas6. As circulating PMP levels were not altered in Gas6 ؊/؊ mice compared with Gas6 ؉/؉ mice, we hypothesize that the Gas6-mediated uptake is not a means to clear the bulk of circulating PMPs but may serve to locally phagocytose PMPs generated at sites of platelet activation and as a way to effect endothelial responses.

show abstract

“…Tabas’s laboratory showed that Axl −/− mice were in fact more susceptible to herpes simplex virus (HSV)-1 infection in vivo (160). This phenotype was ascribed to the reduced capacity of Axl −/− DCs to cross-present viral antigens.…”

Section: Tams In Diseasesmentioning

confidence: 99%

TAM Receptor Signaling in Immune Homeostasis

Rothlin¹,

Silva²,

Bosurgi³

et al. 2015

Annu. Rev. Immunol.

389

407

View full text Add to dashboard Cite

The TAM receptor tyrosine kinases (RTKs)—TYRO3, AXL, and MERTK—together with their cognate agonists GAS6 and PROS1 play an essential role in the resolution of inflammation. Deficiencies in TAM signaling have been associated with chronic inflammatory and autoimmune diseases. Three processes regulated by TAM signaling may contribute, either independently or collectively, to immune homeostasis: the negative regulation of the innate immune response, the phagocytosis of apoptotic cells, and the restoration of vascular integrity. Recent studies have also revealed the function of TAMs in infectious diseases and cancer. Here, we review the important milestones in the discovery of these RTKs and their ligands and the studies that underscore the functional importance of this signaling pathway in physiological immune settings and disease.

show abstract

An AXL/LRP-1/RANBP9 complex mediates DC efferocytosis and antigen cross-presentation in vivo

Cited by 103 publications

References 55 publications

LDL receptor-related protein-1 regulates NFκB and microRNA-155 in macrophages to control the inflammatory response

LDL receptor-related protein-1 regulates NFκB and microRNA-155 in macrophages to control the inflammatory response

The Gas6-Axl Protein Interaction Mediates Endothelial Uptake of Platelet Microparticles

TAM Receptor Signaling in Immune Homeostasis

Contact Info

Product

Resources

About