The spleen is required for the generation of systemic tolerance to apoptotic cells. We have recently shown a specialized set of macrophages residing in the marginal zone region of the red pulp drive immunologic tolerance to apoptotic material and in their absence apoptotic cells induce inflammation and autoimmune reactivity. While it is not known how this occurs on a mechanistic level, we have found apoptotic cells provoke expression of a tryptophan-catabolizing enzyme, indoleamine 2, 3 dioxygenase (IDO), which is critical for immune suppression in a variety of inflammatory settings. Further we discovered blockade of IDO greatly altered the way macrophages and dendritic cells respond to apoptotic cells with increased inflammatory immunity and autoimmune disease activity in lupus-prone animals. Thus the data suggest a novel mechanism whereby IDO activity in macrophages controls both innate and adaptive immunity to apoptotic cells. Our proposed project will examine how apoptotic cells driven IDO activity impacts mTOR signals in marginal zone macrophages, how IDO-driven tryptophan metabolism impacts apoptotic cell-mediated tolerance, and mechanisms by which IDO may influence Treg activation; finally testing these mechanisms in an experimental model of systemic lupus erythematosus. Thus, the findings of this project could have enormous implications in diseases of hypo and hyper-immunity where modulation of the tolerogenic rheostat would provide significant clinical benefit.

Public Health Relevance

Natural cell death is an important modulator of immune reactivity and linked to a variety of diseases of hyper and hypo inflammation. Recently we found a metabolic stress response associated with immune suppression and cancer is activated when the immune system encounters dead cells in the blood filtering organs. Blockade of this pathway with pharmacologic agents resulted in a loss of immune suppressive characteristics indicating, for the first time, that this mechanism may play a role in the regulation of immunity b dead cells and the debris they release. In this proposal we will seek to define the role for this system and determine if its modulation can provide therapeutic benefit in autoimmune disease.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Mancini, Marie
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University Health Network
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M5 2C4
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
Duhlin, Amanda; Chen, Yunying; Wermeling, Fredrik et al. (2016) Selective Memory to Apoptotic Cell-Derived Self-Antigens with Implications for Systemic Lupus Erythematosus Development. J Immunol 197:2618-26
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