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

Abstract

Tolerance to self-antigens present in apoptotic cells is critical to maintain immune-homeostasis and prevent systemic autoimmunity. However, mechanisms that sustain self-tolerance are poorly understood. Here we show that systemic administration of apoptotic cells to mice induced splenic expression of the tryptophan catabolizing enzyme indoleamine 2,3-dioxygenase (IDO). IDO expression was confined to the splenic marginal zone and was abrogated by depletion of CD169 + cells. Pharmacologic inhibition of IDO skewed the immune response to apoptotic cells, resulting in increased proinflammatory cytokine production and increased effector T-cell responses toward apoptotic cell-associated antigens. Presymptomatic lupus-prone MRL lpr/lpr mice exhibited abnormal elevated IDO expression in the marginal zone and red pulp and inhibition of IDO markedly accelerated disease progression. Moreover, chronic exposure of IDO-deficient mice to apoptotic cells induced a lupus-like disease with serum autoreactivity to double-stranded DNA associated with renal pathology and increased mortality. Thus, IDO limits innate and adaptive immunity to apoptotic self-antigens and IDO-mediated regulation inhibits inflammatory pathology caused by systemic autoimmune disease.inflammation | macrophage M acrophages (MΦ) are innate scavenging cells that are important in maintenance of tolerance to self. Mechanistically, it is unknown how MΦs contribute to self-tolerance although it is evident that clearance is necessary and must lead to regulation rather than adaptive immunity. In this vein it has been shown that interaction of apoptotic cells with MΦs results in the induction of an anti-inflammatory response dominated by TGF-β, which suppresses proinflammatory cytokine production (1, 2). However, the molecular mechanisms by which capture of apoptotic cells trigger immune suppression in vivo is unknown. Moreover, known mechanisms, such as exposure of phosphatidyl serine and TGF-β production, do not explain how tolerance is maintained at the molecular level.Apoptotic cells in circulation are trapped and removed in the marginal zone (MZ) of the spleen (3). The MZ is populated by specialized MΦs tightly associated with the reticular meshwork. These MΦ are defined by constitutive expression of either the scavenger macrophage receptor with collagenous structure, MARCO, or the metallophillic macrophage marker, MOMA-1 (4-6). The importance of MZ MΦs (MZMs) in apoptotic cell removal and tolerance was illustrated by our recent findings that their depletion significantly changed the immune response to apoptotic cells altering localization, increasing proinflammatory cytokine production, and enhancing phagocytosis and phagocyte activation (7). Similarly, in related studies deletion of MARCO + and MOMA-1 + MZMs retarded the clearance of apoptotic material and abrogated tolerance to apoptotic cell-associated antigens in a mouse model of experimental autoimmune encephalomyelitis (8). Thus, defective MZM-mediated apoptotic cell capture and removal appears to have sig...

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

“…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.…”

“…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.…”

“…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.…”

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

“…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.…”

“…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).…”