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

作者：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^*

来源：Proceedings of the National Academy of Sciences, 2012, 109(10): 3909-3914.

DOI：10.1073/pnas.1117736109

• inflammation
• macrophage

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 MRLlpr/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.

• 出版日期2012-3-6