02522nas a2200301   4500000000100000008004100001260001200042653000800054653002500062653002000087653002400107653001200131653002200143100001500165700001400180700001200194700001500206700001400221700001500235700001300250700001200263700001600275700001500291245011800306856007300424520170900497022001402206       2020                            d  c10/202010aIDO10aMycobacterium leprae10adendritic cells10alepromatous leprosy10aleprosy10areversal reaction1 aOliveira J1 aGandini M1 aSales J1 aFujimori S1 aBarbosa M1 aFrutuoso V1 aMoraes M1 aSarno E1 aPessolani M1 aPinheiro R00aMycobacterium leprae induces a tolerogenic profile in monocyte-derived dendritic cells via TLR2 induction of IDO.  uhttps://jlb.onlinelibrary.wiley.com/doi/epdf/10.1002/JLB.4A0320-188R3 a<p>The enzyme IDO-1 is involved in the first stage of tryptophan catabolism and has been described in both microbicidal and tolerogenic microenvironments. Previous data from our group have shown that IDO-1 is differentially regulated in the distinctive clinical forms of leprosy. The present study aims to investigate the mechanisms associated with IDO-1 expression and activity in human monocyte-derived dendritic cells (mDCs) after stimulation with irradiated Mycobacterium leprae and its fractions. M. leprae and its fractions induced the expression and activity of IDO-1 in human mDCs. Among the stimuli studied, irradiated M. leprae and its membrane fraction (MLMA) induced the production of proinflammatory cytokines TNF and IL-6 whereas irradiated M. leprae and its cytosol fraction (MLSA) induced an increase in IL-10. We investigated if TLR2 activation was necessary for IDO-1 induction in mDCs. We observed that in cultures treated with a neutralizing anti-TLR2 antibody, there was a decrease in IDO-1 activity and expression induced by M. leprae and MLMA. The same effect was observed when we used a MyD88 inhibitor. Our data demonstrate that coculture of mDCs with autologous lymphocytes induced an increase in regulatory T (Treg) cell frequency in MLSA-stimulated cultures, showing that M. leprae constituents may play opposite roles that may possibly be related to the dubious effect of IDO-1 in the different clinical forms of disease. Our data show that M. leprae and its fractions are able to differentially modulate the activity and functionality of IDO-1 in mDCs by a pathway that involves TLR2, suggesting that this enzyme may play an important role in leprosy immunopathogenesis.</p>  a1938-3673