General control non-repressed 2 (GCN2) is a ser/thr kinase that alters translation in response to various cellular stresses. Recently we published data suggesting that GCN2 is activated in response to apoptotic cell challenge in splenic dendritic cells and macrophages controlling cytokine production, thus suggesting a novel mechanism of tolerance induction dependent on GCN2. In this proposal we will examine how GCN2 influences phagocyte responses to apoptotic cells using mice with a complete or cell specific defects in GCN2 function testing the role of GCN2 and its downstream effector C/EBP homologous protein 10 (CHOP) in apoptotic cell induced cytokine production, phagocyte maturation, antigen presentation to T cells, and ability to suppress adaptive T cell responses and induce long-term tolerance in a skin allograft model. Moreover we will examine the impact of GCN2 disruption on development of lupus in mouse models and will test the ability of the GCN2 activating drug, halofuginone, to inhibit autoimmunity development and disease pathology in animal models of the disease. Thus, the project will provide key mechanistic rationale to explore GCN2 pathway manipulation as a therapeutic target in lupus and other autoimmune diseases. !
Suppression of immunity towards debris created by cell death is critical for prevention of autoimmune disease. Recently we discovered that a regulatory pathway induced in response to amino acid withdrawal is activated when the immune system encounters cell debris in the blood filtering organs. Blockade of this pathway was associated with a loss of immune suppressive characteristics indicating, for the first time, that this mechanism may play a role in the prevention of autoimmunity. In this proposal we will seek to define the role for this amino acid responsive system to cell debris and determine if its activatio can protect individuals from developing lupus.
|Shinde, Rahul; Hezaveh, Kebria; Halaby, Marie Jo et al. (2018) Apoptotic cell-induced AhR activity is required for immunological tolerance and suppression of systemic lupus erythematosus in mice and humans. Nat Immunol 19:571-582|
|McGaha, Tracy L; Karlsson, Mikael C I (2016) Apoptotic cell responses in the splenic marginal zone: a paradigm for immunologic reactions to apoptotic antigens with implications for autoimmunity. Immunol Rev 269:26-43|
|Shinde, Rahul; Shimoda, Michiko; Chaudhary, Kapil et al. (2015) B Cell-Intrinsic IDO1 Regulates Humoral Immunity to T Cell-Independent Antigens. J Immunol 195:2374-82|
|Ravishankar, Buvana; Liu, Haiyun; Shinde, Rahul et al. (2015) The amino acid sensor GCN2 inhibits inflammatory responses to apoptotic cells promoting tolerance and suppressing systemic autoimmunity. Proc Natl Acad Sci U S A 112:10774-9|
|Chaudhary, Kapil; Shinde, Rahul; Liu, Haiyun et al. (2015) Amino acid metabolism inhibits antibody-driven kidney injury by inducing autophagy. J Immunol 194:5713-24|
|Ravishankar, Buvana; Shinde, Rahul; Liu, Haiyun et al. (2014) Marginal zone CD169+ macrophages coordinate apoptotic cell-driven cellular recruitment and tolerance. Proc Natl Acad Sci U S A 111:4215-20|
|McGaha, Tracy L; Madaio, Michael P (2014) Lupus Nephritis: Animal Modeling of a Complex Disease Syndrome Pathology. Drug Discov Today Dis Models 11:13-18|