TAM receptor signaling and autoimmune disease

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The TAM receptor tyrosine kinases Tyro3, Axl, and Mer and their ligands Gas6 and Protein S are essential for the phagocytosis of apoptotic cells and membranes in the adult immune, nervous, and reproductive systems. Genetic studies indicate that this receptor-ligand system is central to apoptotic cell engulfment that is triggered by the ‘eat-me’ signal phosphatidylserine (PtdSer). At the same time, TAM signaling is normally activated by Toll-like receptor (TLR) and type I interferon signaling, as part of the innate inflammatory response in dendritic cells (DCs) and macrophages, where it inhibits this response. Deficiencies in TAM signaling result in human retinal dystrophies and may contribute to lupus and other human autoimmune diseases.

Introduction

Autoimmune diseases arise when the immune system makes the fundamental mistake of confusing self with non-self. Although rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), multiple sclerosis (MS), and other autoimmune disorders have differential presentations, organ and tissue targets, and dependence on cellular versus humoral immunity, each is characterized by chronic inflammation and autoreactivity. SLE is a particularly illustrative example of the challenges of both understanding and treating autoimmune disease. This broad-spectrum disorder is characterized prominently by the presence of autoantibodies directed against nuclear antigens such as ribonucleoproteins and double-stranded DNA. Although the etiology and pathogenesis of SLE remain to be defined, it is increasingly evident that impaired clearance of apoptotic cells, enhanced activation of dendritic cells (DCs), and a concomitant type I interferon (IFN) response are associated with, and almost certainly contribute to, autoimmunity [1, 2, 3]. The first of these defects represents an especially serious threat, since programmed cell death and the generation of apoptotic cells are central to cellular turnover and tissue homeostasis during adulthood. While in some cases apoptotic cells appear to be shed; for example, as occurs with intestinal epithelial cells and epidermal keratinocytes, most such cells must be actively cleared by phagocytes. Defects in apoptotic cell clearance can lead to the accumulation of intracellular components and the aberrant (sustained) exposure of nuclear antigens to the immune system. This can lead, in turn, to the activation of autoreactive B cells, autoantibody production, and the formation of immune complexes. Immune complexes of DNA and RNA are known to activate DCs and to trigger the production of type I IFNs, which perpetuate a cycle of immune activation [4]. The pathogenic role of type I IFNs in autoimmunity is highlighted by the observed amelioration of disease in lupus-prone mice that lack the type I IFN receptor (IFNAR) [5]. Thus, SLE may be driven by the pathologic exposure to self-antigens due to the aberrant clearance of apoptotic cells, which in turn leads to the unabated activation of DCs and the subsequent production of type I IFNs. Recent studies on the function of the TAM family of receptor tyrosine kinases have provided important insights into these two discrete, but tightly linked phenomena  the removal of apoptotic cells and the regulation of DC activation and the type I IFN response. In this review, we summarize findings from these studies, and highlight their potential importance to SLE specifically and to human autoimmune disease in general.

Section snippets

TAM receptors and ligands

The TAM receptor tyrosine kinases, Tyro3, Axl, and Mer, were identified as a distinct receptor protein-tyrosine kinase subfamily in 1991 [6•, 7]. The TAMs share a characteristic tandem arrangement of two immunoglobulin-like and two fibronectin type III repeats in their extracellular, ligand-binding domains, which are followed by a single-pass transmembrane domain and a cytoplasmatic protein-tyrosine kinase [8]. The TAM receptors remained orphans, in the sense that their activating ligands were

TAM signaling and apoptotic cell clearance

Significant progress in our understanding of the biological role of the TAM pathway was made possible with the generation of mice lacking Tyro3, Axl, and Mer [24•, 25•], and both TAM ligands [26, 27, 28, 29]. In agreement with the ability of TAM ligands to bind both to PtdSer exposed on the extracellular surface of apoptotic cells and to the TAM receptors expressed by phagocytes [8], a plethora of degenerative phenotypes that result from the inefficient phagocytosis of apoptotic cells and

Linking TAM-dependent apoptotic cell clearance to TAM regulation of the inflammatory response

In addition to playing an essential role in the turnover of apoptotic cells and membranes in adult tissues, TAM signaling has been found to play a fundamental role in the regulation of the innate immune response. Camenisch and colleagues were the first to describe the excessive production of TNFα in response to LPS administration together with an associated increased sensitivity to LPS-induced endotoxic shock in Mer KO mice [25]. Consistent with this finding, the activation of murine antigen

TAM signaling and autoimmunity

Perhaps not surprisingly, the delayed clearance of apoptotic cells and the loss of regulation of the inflammatory response are associated with the development of a lupus-like syndrome in TAM KO mice [53••, 54••]. TAM triple knock out (TKO) mice display profound lymphoproliferation and features of systemic autoimmunity [54••]. The peripheral lymphoid organs of these mice become grossly enlarged, due to the expansion of both myeloid and lymphoid cell populations [42••, 54••]. In addition, high

Concluding remarks and future directions

TAM signaling has been found to be a central player in the phagocytosis of the outer segments of PR and apoptotic germ cells. Yet, the specificity of the TAM pathway in the phagocytosis mediated by professional phagocytes, which are known to express a variety of phagocytic receptors, remains unknown. As proposed by Medzhitov [63], apoptotic cells may produce signals that are associated with the type of death that they have undergone, which might in turn determine the type of phagocytic

Note added in proof

Recent work by Rahman et al. shows the critical role played by Mer in the clearance of apoptotic cells by TBMs in germinal centers [66].

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

Work in the authors’ laboratories is supported by grants from the NIH (AI089824 to CVR and AI077058 to GL), the American Heart Association (0835404N to CVR), the Crohn's and Colitis Foundation of America (2686 to CVR), DTRA (08-1-0009 to GL), and the Ipsen Foundation (to GL).

References (66)

  • N. Tibrewal et al.

    Autophosphorylation docking site Tyr-867 in Mer receptor tyrosine kinase allows for dissociation of multiple signaling pathways for phagocytosis of apoptotic cells and down-modulation of lipopolysaccharide-inducible NF-kappaB transcriptional activation

    J Biol Chem

    (2008)
  • G. Gautier et al.

    A type I interferon autocrine-paracrine loop is involved in Toll-like receptor-induced interleukin-12p70 secretion by dendritic cells

    J Exp Med

    (2005)
  • S. Wormald et al.

    The negative regulatory roles of suppressor of cytokine signaling proteins in myeloid signaling pathways

    Curr Opin Hematol

    (2007)
  • R. Hanayama et al.

    Autoimmune disease and impaired uptake of apoptotic cells in MFG-E8-deficient mice

    Science

    (2004)
  • Rahman ZS, Shao WH, Khan TN, Zhen Y, Cohen PL: Impaired Apoptotic cell clearance in the germinal center by...
  • U.S. Gaipl et al.

    Clearance of apoptotic cells in human SLE

    Curr Dir Autoimmun

    (2006)
  • L. Ronnblom et al.

    The innate immune system in SLE: type I interferons and dendritic cells

    Lupus

    (2008)
  • A. Marshak-Rothstein et al.

    Immunologically active autoantigens: the role of toll-like receptors in the development of chronic inflammatory disease

    Annu Rev Immunol

    (2007)
  • M.L. Santiago-Raber et al.

    Type-I interferon receptor deficiency reduces lupus-like disease in NZB mice

    J Exp Med

    (2003)
  • J.P. O’Bryan et al.

    axl, a transforming gene isolated from primary human myeloid leukemia cells, encodes a novel receptor tyrosine kinase

    Mol Cell Biol

    (1991)
  • G. Lemke et al.

    Immunobiology of the TAM receptors

    Nat Rev Immunol

    (2008)
  • T.N. Stitt et al.

    The anticoagulation factor protein S and its relative, Gas6, are ligands for the Tyro 3/Axl family of receptor tyrosine kinases

    Cell

    (1995)
  • M.R. Mark et al.

    Characterization of Gas6, a member of the superfamily of G domain-containing proteins, as a ligand for Rse and Axl

    J Biol Chem

    (1996)
  • M. Huang et al.

    Structural basis of membrane binding by Gla domains of vitamin K-dependent proteins

    Nat Struct Biol

    (2003)
  • K.S. Ravichandran et al.

    Engulfment of apoptotic cells: signals for a good meal

    Nat Rev Immunol

    (2007)
  • G. Lemke et al.

    TAM receptors and the clearance of apoptotic cells

    Ann N Y Acad Sci

    (2010)
  • D. Prasad et al.

    TAM receptor function in the retinal pigment epithelium

    Mol Cell Neurosci

    (2006)
  • S.M. Rezende et al.

    Coagulation, inflammation, and apoptosis: different roles for protein S and the protein S-C4b binding protein complex

    Blood

    (2004)
  • F. Niessen et al.

    Dendritic cell PAR1-S1P3 signalling couples coagulation and inflammation

    Nature

    (2008)
  • Q. Lu et al.

    Tyro-3 family receptors are essential regulators of mammalian spermatogenesis

    Nature

    (1999)
  • T.D. Camenisch et al.

    A novel receptor tyrosine kinase, Mer, inhibits TNF-alpha production and lipopolysaccharide-induced endotoxic shock

    J Immunol

    (1999)
  • T. Burstyn-Cohen et al.

    Lack of Protein S in mice causes embryonic lethal coagulopathy and vascular dysgenesis

    J Clin Invest

    (2009)
  • A. Angelillo-Scherrer et al.

    Deficiency or inhibition of Gas6 causes platelet dysfunction and protects mice against thrombosis

    Nat Med

    (2001)
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