Indolamine 2,3‐dioxygenase is expressed in the CNS and down‐regulates autoimmune inflammation

Abstract

The tryptophan (trp)-catabolizing enzyme indolamine 2,3-dioxygenase (IDO) is induced by the T helper 1 (Th 1) cytokine IFN-gamma during infections in various tissues including the brain. Recent studies demonstrated an immune modulatory function of this enzyme, since IDO-mediated depletion of trp hinders T cell proliferation, while its inhibition by 1-methyl-tryptophan (1-Mt) induces breakdown of immune tolerance in the placenta, leading to rejection of allogeneic concepti. Here, we tested IDO expression and function during experimental autoimmune encephalomyelitis (EAE) actively induced in adult SJL mice by immunization with PLP139-151. IDO activity (determined by HPLC analysis of the kynurenine/tryptophan ratio) was increased in the spleen during the preclinical phase, and within the brain and spinal cord at the onset of symptoms. Immunocytochemistry revealed macrophages/activated microglia expressing IDO during EAE and in vitro experiments confirmed IDO induction in microglia upon IFN-gamma treatment with synergistic effects of TNF-alpha. Inhibition of IDO by systemic administration of 1-Mt at clinical onset significantly exacerbated disease scores. From these data, it is tempting to speculate that IFN-gamma from encephalitogenic Th 1 cells induces local IDO expression, thereby initiating a negative feedback loop which may underlie the self-limitation of autoimmune inflammation during EAE and multiple sclerosis.

Function of indoleamine 2,3‐dioxygenase in corneal allograft rejection and prolongation of allograft survival by over‐expression

“…In comparison to placenta, we found that a low level of IDO was expressed in cornea. Consistent with published findings in brain microvascular endothelial cells [22] and microglia [23], we found that IDO was inducible in cornea by inflammatory mediators. In particular, TNF acted synergistically with IFN-c to enhance IDO expression [23,24].…”

Indoleamine 2,3 dioxygenase–mediated tryptophan catabolism regulates accumulation of Th1/Th17 cells in the joint in collagen‐induced arthritis

“…This interpretation is supported by our finding that inhibition of IDO by 1-MT after arthritis onset exacerbates CIA. It is also consistent with a series of studies in EAE (12,13) and with a previous study by Szanto et al (14) demonstrating that inhibition of IDO before arthritis onset, but at a time when IDO up-regulation is observed, also exacerbated CIA.…”

“…tryptophan degradation by the nonspecific inhibitor 1-methyltryptophan (1-MT) exacerbates EAE and collagen-induced arthritis (CIA) (12)(13)(14). Conversely, administration of 3-DAA, a synthetic analog of the tryptophan metabolite 3-hydroxyanthranyllic acid, ameliorates EAE and CIA (15,16).…”

Lipopolysaccharide-induced depressive-like behavior is mediated by indoleamine 2,3-dioxygenase activation in mice

“…1-MT, a competitive inhibitor of IDO, blocks human dendritic cell regulatory function in vitro 21 and functions in vivo to block IDO-mediated immune events in animal models of rheumatoid arthritis, 22 type 1 diabetes 23 and multiple sclerosis. 24 We show here that inhibition of IDO activation with either approach fully abrogates LPS-induced depressive like behavior.…”