Tolerance to apoptotic cells is regulated by indoleamine 2,3-dioxygenase

Ravishankar, Buvana; Liu, Haiyun; Shinde, Rahul; Chandler, Phillip; Baban, Babak; Tanaka, Masato; Munn, David H.; Mellor, Andrew L.; Karlsson, Mikael C. I.; McGaha, Tracy L.

doi:10.1073/pnas.1117736109

Cited by 165 publications

(225 citation statements)

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“…CD300f-deficient mice developed a more severe autoimmune inflammation than the WT mice, when the mice were stressed with excess AC in the pristane-induced autoimmune disease model, which fits the fact that repeated exposure to AC leads to exacerbated disease in autoimmune-prone mice. 7,35,36 Moreover, our previous study showed that CD300f-deficient Fcgr2b −/− mice are predisposed to develop more severe splenomegaly and have a higher fatality rate than in Fcgr2b −/− mice. 29 Here we performed an in-depth analysis to identify cellular and molecular abnormalities behind this predisposition.…”

Section: Resultsmentioning

confidence: 99%

“…Although CD300f-deficient mice did not develop an overt immune phenotype, nor did they accumulate elevated levels of AC, we hypothesized that continuous exposure to AC could tip the balance towards autoimmunity, as repeated exposure to AC debris has been shown to exacerbate disease in autoimmune-prone mice, but not in normal mice. 7,35,36 Therefore, we injected AC into WT and CD300f-deficient mice, in the presence of pristane, an alkane that induces a SLE-like disease by promoting the release of auto-antigens from AC. 37,38 Although pristane alone did not cause any difference in splenomegaly between Cd300f +/+ and Cd300f CD300f deficiency causes an accelerated autoimmune response in Fcgr2b −/− mice.…”

Section: Resultsmentioning

confidence: 99%

“…3 Moreover, recognition and engulfment of AC by macrophages and DC serves to sustain immune tolerance to self-antigens by virtue of the anti-inflammatory cytokines IL-10 and TGF-β released from these cells, and the recruitment of natural regulatory T cells. [4][5][6][7] Post AC engulfment, macrophages appear to be capable of fully digesting AC-associated antigens and limit their access to antigen presentation compartments, and therefore are inefficient at T-cell priming. 8 In contrast, DC are highly efficient at processing and presentation of engulfed antigens, using either direct or cross-presentation pathways, which either anergizes or activates potentially self-reactive T cells, depending on the context of antigen presentation.…”

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Enhanced efferocytosis by dendritic cells underlies memory T-cell expansion and susceptibility to autoimmune disease in CD300f-deficient mice

Tian

Lee

et al. 2016

Cell Death Differ

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Homeostasis requires the immunologically silent clearance of apoptotic cells before they become pro-inflammatory necrotic cells. CD300f (CLM-1) is a phosphatidylserine receptor known to positively regulate efferocytosis by macrophages, and CD300f genedeficient mice are predisposed to develop a lupus-like disease. Here we show that, in contrast to CD300f function in macrophages, its expression inhibits efferocytosis by DC, and its deficiency leads to enhanced antigen processing and T-cell priming by these DC. The consequences are the expansion of memory T cells and increased ANA levels in aged CD300f-deficient mice, which predispose CD300f-deficient mice to develop an overt autoimmune disease when exposed to an overload of apoptotic cells, or an exacerbated autoimmunity when combined with FcγRIIB deficiency. Thus, our data demonstrates that CD300f helps to maintain immune homeostasis by promoting macrophage clearance of self-antigens, while conversely inhibiting DC uptake and presentation of self-antigens.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

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Enhanced efferocytosis by dendritic cells underlies memory T-cell expansion and susceptibility to autoimmune disease in CD300f-deficient mice

Tian

Lee

et al. 2016

Cell Death Differ

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“…Likewise, we have reported that apoptotic cells drive rapid expression of the tryptophan (Trp)-metabolizing enzyme indoleamine 2,3 dioxygenase 1 (IDO1) in MARCO + marginal zone (MZ) MΦs that is critical for prevention of apoptotic cell-driven autoimmunity (6). Moreover, studies by our group (6) and Sharma et al (9) have shown a link between a loss of IDO1 activity and exaggeration of autoimmune pathology in MRL lpr/lpr mice.…”

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confidence: 98%

“…Macrophages (MΦ) are key drivers of the early innate response to apoptotic cells (4,5), and recent work has shown that tissue-resident MΦs are responsible for initial IL-10 production, promoting regulatory adaptive immunity to apoptotic cell antigens and prevention of inflammatory autoimmunity (4,6,7).…”

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confidence: 99%

The amino acid sensor GCN2 inhibits inflammatory responses to apoptotic cells promoting tolerance and suppressing systemic autoimmunity

Ravishankar

Liu

Shinde

et al. 2015

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

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123

127

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Efficient apoptotic cell clearance and induction of immunologic tolerance is a critical mechanism preventing autoimmunity and associated pathology. Our laboratory has reported that apoptotic cells induce tolerance by a mechanism dependent on the tryptophan catabolizing enzyme indoleamine 2,3 dioxygenase 1 (IDO1) in splenic macrophages (MΦ). The metabolic-stress sensing protein kinase GCN2 is a primary downstream effector of IDO1; thus, we tested its role in apoptotic cell-driven immune suppression. In vitro, expression of IDO1 in MΦs significantly enhanced apoptotic celldriven IL-10 and suppressed IL-12 production in a GCN2-dependent mechanism. Suppression of IL-12 protein production was due to attenuation of IL-12 mRNA association with polyribosomes inhibiting translation while IL-10 mRNA association with polyribosomes was not affected. In vivo, apoptotic cell challenge drove a rapid, GCN2-dependent stress response in splenic MΦs with increased IL-10 and TGF-β production, whereas myeloid-specific deletion of GCN2 abrogated regulatory cytokine production with provocation of inflammatory T-cell responses to apoptotic cell antigens and failure of long-tolerance induction. Consistent with a role in prevention of apoptotic cell driven autoreactivity, myeloid deletion of GCN2 in lupus-prone mice resulted in increased immune cell activation, humoral autoimmunity, renal pathology, and mortality. In contrast, activation of GCN2 with an agonist significantly reduced anti-DNA autoantibodies and protected mice from disease. Thus, this study implicates a key role for GCN2 signals in regulating the tolerogenic response to apoptotic cells and limiting autoimmunity.immunometabolism | stress | tolerance | autoimmunity | apoptosis M ultiple lines of evidence suggest that apoptotic cells are a major source of autoantigens in the autoimmune disease systemic lupus erythematosus (SLE). This evidence includes the fact that the dominant autoantigens targeted in SLE are largely nuclear components that are exposed on apoptotic blebs (1, 2). Moreover, the body of evidence suggests that increased cell death and defective clearance are primary drivers of SLE development and progression (3).In homeostatic conditions, apoptotic cells drive suppressive innate and adaptive tolerogenic immune responses that protect against initiation of inflammatory autoimmunity. Macrophages (MΦ) are key drivers of the early innate response to apoptotic cells (4, 5), and recent work has shown that tissue-resident MΦs are responsible for initial IL-10 production, promoting regulatory adaptive immunity to apoptotic cell antigens and prevention of inflammatory autoimmunity (4, 6, 7).On a molecular level, the mechanisms driving the initial tolerogenic response of myeloid cells to apoptotic material in vivo are poorly defined, although studies suggest a direct role for inhibitory signaling via the MAPK pathway (8), and a recent report indicated that responses to cytoplasmic DNA may be a key mechanism of tolerance to self (9). Likewise, we have reported that apoptoti...

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Targeting Lymphoid Tissues to Promote Immune Tolerance

Chen

Sun

2021

Advanced Therapeutics

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The enormous research progress in autoimmune disorders makes the establishment of long-term clinical tolerance to autoantigens an accessible goal. This strategy endows lymphoid tissues with the tolerogenic ability to induce an unresponsive state toward autoantigens. Lymphoid tissues, as the crossroads, play integral roles in initiating immune activation and immunoregulation. Enormous efforts have driven the exploration of targeting delivery of tolerogenic agents to lymphoid tissues to reverse autoimmune disorders. Herein, the development of various tolerogenic therapies for autoimmune diseases are reviewed, the mechanisms of action from various lymphoid tissues to appropriate cell types by different administration routes are highlighted, and examples of lymphoid tissue-targeting strategies to improve tolerogenic therapy potency are discussed. First lymph nodes-targeting strategies for tolerance induction after interstitial or intra-lymph node (i.LN) injection are summarized, then liver and spleen-mediated tolerance after intravenous administration are described, and finally oral tolerance-based therapies are discussed. It is envisioned that tolerogenic therapy will emerge as a novel treatment for autoimmune diseases.

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Tolerance to apoptotic cells is regulated by indoleamine 2,3-dioxygenase

Cited by 165 publications

References 38 publications

Enhanced efferocytosis by dendritic cells underlies memory T-cell expansion and susceptibility to autoimmune disease in CD300f-deficient mice

Enhanced efferocytosis by dendritic cells underlies memory T-cell expansion and susceptibility to autoimmune disease in CD300f-deficient mice

The amino acid sensor GCN2 inhibits inflammatory responses to apoptotic cells promoting tolerance and suppressing systemic autoimmunity

Targeting Lymphoid Tissues to Promote Immune Tolerance

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