TAM Receptor Signaling in Immune Homeostasis

Rothlin, Carla V.; Silva, Eugenio Antonio Carrera; Bosurgi, Lidia; Ghosh, Sourav

doi:10.1146/annurev-immunol-032414-112103

Cited by 394 publications

(442 citation statements)

References 192 publications

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“…To further determine whether engulfment of other apoptotic cells induces a reparative macrophage phenotype that benefits hematoma clearance and brain recovery after ICH, thrombinstimulated macrophages were incubated with apoptotic neutrophils or T cells for 6 hours. Indeed, in agreement with previous findings (20,54), the addition of apoptotic neutrophils or T cells decreased TNF expression in macrophages; however, HMOX1 expression was not increased by the engulfment of apoptotic leukocytes (Supplemental Figure 8, A and B). Thus, the tissuespecific reparative phenotype of macrophages after ICH is dependent on the efferocytosis of eryptotic erythrocytes.…”

Section: Discussionsupporting

confidence: 92%

“…In this context, phagocytosis is carefully regulated by a suite of scavenger receptors that recognize "eat me" signals expressed by apoptotic cells, including externalization of phosphatidylserine (PtdSer) (18,19). The tyrosine kinases AXL and MERTK are PtdSer receptors activated by the binding of PtdSer-expressing cells via the adaptor proteins GAS6 and protein S (20). Upon activation, AXL/MERTK not only facilitate the action of efferocytosis but also trigger antiinflammatory responses in macrophages by inhibiting Toll-like receptor (TLR) signaling and increasing the expression of suppressor of cytokine 1 (SOCS1) and SOCS3 (21,22).…”

Section: Resultsmentioning

confidence: 99%

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Erythrocyte efferocytosis modulates macrophages towards recovery after intracerebral hemorrhage

Chang¹,

Goods²,

Askenase³

et al. 2017

Journal of Clinical Investigation

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140

161

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-/-bone marrow chimeras (BMCs) at days 7 and 15 after ICH. Right: Quantification of residual hematoma volume in the WT and Ccr2 -/-BMCs. n = 11 at day 7; n = 9 at day 15. *P < 0.05 by Student's t test. (B) Cylinder test and apomorphine turning test from WT and Ccr2 -/-BMCs at day 15 after ICH. n = 6/group for cylinder test; n = 8/ group for apomorphine turning test. *P < 0.05 by Student's t test. (C) Cylinder test, neurological deficit score, and corner test in control-and anti-CCR2 antibody-treated mice at days 1 and 3 after collagenase ICH. n = 7/group. *P < 0.05 by 1-way repeated-measures ANOVA and Bonferroni's post hoc test. (D) Top: Representative coronal sections show hematoma from control-and anti-CCR2 antibody-treated WT mice after blood injection ICH at 7 days. Bottom: Quantification of hematoma volume, n = 3/ group. *P < 0.05 versus control by Student's t test. (E) Top: Representative coronal sections show hematoma in the isotype control-and anti-CCR2 antibody-treated mice from collagenase model at day 12. Bottom: Quantification of hematoma volume. n = 8/group. *P < 0.05 versus control by Student's t test. (F) The cylinder test, neurological deficit score, and corner test in isotype control-and anti-CCR2 antibody-treated ICH mice at days 3, 5, 7, 9, and 11 after collagenase ICH surgery. n = 8/group. *P < 0.05 versus isotype control group by 1-way repeated-measures ANOVA and Bonferroni's post hoc test. αCCR2, anti-CCR2 antibody.

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Section: Discussionsupporting

confidence: 92%

Section: Resultsmentioning

confidence: 99%

Erythrocyte efferocytosis modulates macrophages towards recovery after intracerebral hemorrhage

Chang¹,

Goods²,

Askenase³

et al. 2017

Journal of Clinical Investigation

Self Cite

140

161

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“…Tyro3-Axl-MerTK (TAM) receptors on myeloid cells, including MerTK, act as a fascinating bridge between two key resolution functions, efferocytosis and suppression of inflammation (38). In particular, MerTK not only mediates efferocytosis, but also triggers signaling responses that dampen inflammation (14,30,(39)(40)(41)(42)(43)(44)(45).…”

Section: Discussionmentioning

confidence: 99%

MerTK cleavage limits proresolving mediator biosynthesis and exacerbates tissue inflammation

Cai

Thorp

Doran

et al. 2016

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

184

201

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The acute inflammatory response requires a coordinated resolution program to prevent excessive inflammation, repair collateral damage, and restore tissue homeostasis, and failure of this response contributes to the pathology of numerous chronic inflammatory diseases. Resolution is mediated in part by long-chain fatty acid-derived lipid mediators called specialized proresolving mediators (SPMs). However, how SPMs are regulated during the inflammatory response, and how this process goes awry in inflammatory diseases, are poorly understood. We now show that signaling through the Mer proto-oncogene tyrosine kinase (MerTK) receptor in cultured macrophages and in sterile inflammation in vivo promotes SPM biosynthesis by a mechanism involving an increase in the cytoplasmic:nuclear ratio of a key SPM biosynthetic enzyme, 5-lipoxygenase. This action of MerTK is linked to the resolution of sterile peritonitis and, after ischemia-reperfusion (I/R) injury, to increased circulating SPMs and decreased remote organ inflammation. MerTK is susceptible to ADAM metallopeptidase domain 17 (ADAM17)-mediated cellsurface cleavage under inflammatory conditions, but the functional significance is not known. We show here that SPM biosynthesis is increased and inflammation resolution is improved in a new mouse model in which endogenous MerTK was replaced with a genetically engineered variant that is cleavage-resistant (Mertk CR ). Mertk CR mice also have increased circulating levels of SPMs and less lung injury after I/R. Thus, MerTK cleavage during inflammation limits SPM biosynthesis and the resolution response. These findings contribute to our understanding of how SPM synthesis is regulated during the inflammatory response and suggest new therapeutic avenues to boost resolution in settings where defective resolution promotes disease progression.MerTK | efferocytosis | inflammation resolution | macrophages | 5-lipoxygenase

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“…Furthermore, whereas the functions of GAS6 seem to be limited to those caused by activation of the TAM receptors, PROS1 has TAM receptor-dependent and independent activities (8,(10)(11)(12). In line with their discrete properties, GAS6 and PROS1 were shown to control distinct immune mechanisms in vitro and in vivo (7).…”

mentioning

confidence: 97%

“…Recently, the TAM receptors: TYRO3, AXL, and MERTK and their ligands: growth arrest-specific 6 (GAS6) and protein S (PROS1) were shown to play a critical role in the resolution of inflammation (7). This is achieved by the ability of TAM signaling to down-regulate innate inflammatory responses, mediate efferocytosis, and restore vascular integrity (8).…”

mentioning

confidence: 99%

GAS6 is a key homeostatic immunological regulator of host–commensal interactions in the oral mucosa

Nassar

Tabib

Capucha

et al. 2017

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

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The oral epithelium contributes to innate immunity and oral mucosal homeostasis, which is critical for preventing local inflammation and the associated adverse systemic conditions. Nevertheless, the mechanisms by which the oral epithelium maintains homeostasis are poorly understood. Here, we studied the role of growth arrest specific 6 (GAS6), a ligand of the TYRO3–AXL–MERTK (TAM) receptor family, in regulating oral mucosal homeostasis. Expression of GAS6 was restricted to the outer layers of the oral epithelium. In contrast to protein S, the other TAM ligand, which was constitutively expressed postnatally, expression of GAS6 initiated only 3–4 wk after birth. Further analysis revealed that GAS6 expression was induced by the oral microbiota in a myeloid differentiation primary response gene 88 (MyD88)-dependent fashion. Mice lacking GAS6 presented higher levels of inflammatory cytokines, elevated frequencies of neutrophils, and up-regulated activity of enzymes, generating reactive nitrogen species. We also found an imbalance in Th17/Treg ratio known to control tissue homeostasis, as Gas6-deficient dendritic cells preferentially secreted IL-6 and induced Th17 cells. As a result of this immunological shift, a significant microbial dysbiosis was observed in Gas6−/− mice, because anaerobic bacteria largely expanded by using inflammatory byproducts for anaerobic respiration. Using chimeric mice, we found a critical role for GAS6 in epithelial cells in maintaining oral homeostasis, whereas its absence in hematopoietic cells synergized the level of dysbiosis. We thus propose GAS6 as a key immunological regulator of host–commensal interactions in the oral epithelium.

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TAM Receptor Signaling in Immune Homeostasis

Cited by 394 publications

References 192 publications

Erythrocyte efferocytosis modulates macrophages towards recovery after intracerebral hemorrhage

Erythrocyte efferocytosis modulates macrophages towards recovery after intracerebral hemorrhage

MerTK cleavage limits proresolving mediator biosynthesis and exacerbates tissue inflammation

GAS6 is a key homeostatic immunological regulator of host–commensal interactions in the oral mucosa

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