A novel role for c-Src and STAT3 in apoptotic cell–mediated MerTK-dependent immunoregulation of dendritic cells

Yi, Zuoan; Li, Li; Matsushima, Glenn K.; Earp, H. Shelton; Wang, Bo; Tisch, Roland

doi:10.1182/blood-2009-03-207522

Cited by 35 publications

(39 citation statements)

References 56 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Apoptotic cells flip phosphatidylserine, normally located on the inner membrane, to the outer bilayer and binding to MerTK receptors on APCs induces active downregulation of NF-kB. 34,35 NF-kB activation in DCs is critical for the upregulation of proinflammatory cytokines and costimulatory molecules, and its inhibition is a promising approach to reduce T-cell activation in GVHD. 15,[36][37][38][39][40][41] In our model, the uptake of ECP-induced apoptotic cells significantly reduced NF-kB activation in host DCs.…”

Section: Discussionmentioning

confidence: 99%

Autologous apoptotic cells preceding transplantation enhance survival in lethal murine graft-versus-host models

Florek

Sega

Leveson-Gower

et al. 2014

Blood

View full text Add to dashboard Cite

Key Points• Prophylactic ECP protects against GVHD in a murine BMT model.• ECP provides apoptotic signals that promote tolerance through dendritic cells and Tregs.Acute graft-versus-host disease (GVHD) is induced by alloreactivity of donor T cells toward host antigens presented on antigen-presenting cells (APCs). Apoptotic cells are capable of inducing tolerance by altering APC maturation. Apoptosis can be induced by extracorporeal photopheresis (ECP). We demonstrate that the use of ECP as a prophylaxis prior to conditioning significantly improves survival (P < .0001) after bone marrow transplantation (BMT) by inhibiting the initiation phase of acute GVHD in a murine BMT model. ECP-treated autologous splenocytes resulted in immune tolerance in the host, including reduced dendritic cell activation with decreased nuclear factor-kB engagement, increased regulatory T-cell (Treg) numbers with enhanced expression of cytolytic T lymphocyte-associated antigen 4, potentiating their suppressive function. The protective effect required host production of interleukin-10 and host Tregs. Conventional T cells that entered this tolerant environment experienced reduced proliferation, as well as a reduction of tissue homing and expression of activation markers. The induction of this tolerant state by ECP was obviated by cotreatment with lipopolysaccharide, suggesting that the inflammatory state of the recipient prior to treatment would play a role in potential clinical translation. The use of prophylactic ECP may provide an alternative and safe method for immunosuppression in the bone marrow transplant setting. (Blood.

show abstract

Section: Discussionmentioning

confidence: 99%

Autologous apoptotic cells preceding transplantation enhance survival in lethal murine graft-versus-host models

Florek

Sega

Leveson-Gower

et al. 2014

Blood

View full text Add to dashboard Cite

show abstract

“…These receptors share ligand specificity for growth arrest gene 6 (Gas6) and protein S (ProS) and are best known for their role in the recognition and phagocytosis of apoptotic cells (270, 271). In DCs, which express both Axl and Mer, TAM receptors transduce inhibitory signals upon recognition of apoptotic cells (273–275). They also negatively regulate TLR signals (272).…”

Section: Steady-state Cytokines Toll-like Receptors and Their Signamentioning

confidence: 99%

Molecular Control of Steady-State Dendritic Cell Maturation and Immune Homeostasis

Hammer

Ma²

2013

Annu. Rev. Immunol.

137

111

View full text Add to dashboard Cite

Dendritic cells (DCs) are specialized sentinels responsible for coordinating adaptive immunity. This function is dependent upon coupled sensitivity to environmental signs of inflammation and infection to cellular maturation—the programmed alteration of DC phenotype and function to enhance immune cell activation. Although DCs are thus well equipped to respond to pathogens, maturation triggers are not unique to infection. Given that immune cells are exquisitely sensitive to the biological functions of DCs, we now appreciate that multiple layers of suppression are required to restrict the environmental sensitivity, cellular maturation, and even life span of DCs to prevent aberrant immune activation during the steady state. At the same time, steady-state DCs are not quiescent but rather perform key functions that support homeostasis of numerous cell types. Here we review these functions and molecular mechanisms of suppression that control steady-state DC maturation. Corruption of these steady-state operatives has diverse immunological consequences and pinpoints DCs as potent drivers of autoimmune and inflammatory disease.

show abstract

“…Mer deficient mice develop a lupus-like autoimmune syndrome, which most likely results from Mer-mediated inflammatory response with skewed cytokine production and impaired engulfment of apoptotic cells [8; 16; 17]. Mer receptor signaling induces an inhibitory pathway in macrophages regulating TNF-α production through blockage of NF-κB cascade [16; 18]. The expression pattern of Mer has been reported mostly within the monocytic cell lineage with imbalanced tissue distribution.…”

Section: Introductionmentioning

confidence: 99%

A protective role of Mer receptor tyrosine kinase in nephrotoxic serum-induced nephritis

Shao

Zhen

Rosenbaum

et al. 2010

Clinical Immunology

View full text Add to dashboard Cite

The Mer receptor tyrosine kinase is strongly expressed in the glomerulus. We wondered if this molecule might modify immune-mediated glomerular disease through its functions as a receptor for apoptotic cells and immunoregulatory molecule. Mer-knockout (KO) mice showed decreased survival rate and greatly increased proteinuria and serum urea levels compared to wild type (WT) mice by day 3 after injection of NTS. Their glomeruli were hyperplastic and later became necrotic. While in the glomerulus of WT mice, a significant increase of Mer expression was observed. Apoptotic bodies were evident in NTS-treated Mer-KO kidneys, but not in normal controls. NTStreated Mer-KO mice had massive neutrophil infiltration and inflammatory cytokine expression. Mer thus has a critical role in attenuating renal inflammation, both as a receptor for apoptotic cells and as a molecule that down regulates inflammation.

show abstract

A novel role for c-Src and STAT3 in apoptotic cell–mediated MerTK-dependent immunoregulation of dendritic cells

Cited by 35 publications

References 56 publications

Autologous apoptotic cells preceding transplantation enhance survival in lethal murine graft-versus-host models

Autologous apoptotic cells preceding transplantation enhance survival in lethal murine graft-versus-host models

Molecular Control of Steady-State Dendritic Cell Maturation and Immune Homeostasis

A protective role of Mer receptor tyrosine kinase in nephrotoxic serum-induced nephritis

Contact Info

Product

Resources

About