IL-12/23p40 overproduction by dendritic cells leads to an increased Th1 and Th17 polarization in a model of Yersinia enterocolitica-induced reactive arthritis in TNFRp55-/- mice

ANDREA CONSTANZA MAYORDOMO; JUAN EDUARDO SILVA; CAROLINA VIRGINIA GORLINO; JOSÉ LUIS ARIAS; WALTER BERÓN; MARÍA SILVIA DI GENARO

PLOS ONE

PUBLIC LIBRARY SCIENCE

Lugar: San Francisco; Año: 2018 vol. 13

1932-6203

Dendritic cells (DCs) play critical functions in the initiation of immune responses. Understandingtheir role in reactive arthritis (ReA) will help delineate the pathogenesis ofthis arthropathy. In early studies, we detected IL-12/23p40 deregulation in Yersinia entercolitica(Ye)-induced ReA in TNFRp55-deficient (TNFRp55-/-) mice. In this study, weassessed the contribution of DCs in this overproduction. First, greater levels of IL-12/23p40, IFN-γand IL-17A were confirmed in supernatants of lipopolysaccharide (LPS)-stimulatedTNFRp55-/-splenocytes obtained on arthritis onset (day 14 after Ye infection).Later, DCs were identified as a precise source of IL-12/23p40 since increased frequencyof splenic IL-12/23p40+DCs was detected in TNFRp55-/- mice. After robust in vivo amplificationof DCs by injection of Fms-like tyrosine kinase 3-Ligand (Flt3L)-transfected BL16melanoma, DCs were purified. These cells recapitulated the higher production of IL-12/23p40 under TNFRp55deficiency. In agreement with these results, TNFRp55-/- DCs promotedTh1 and Th17 programs by co-culture with WT CD4+lymphocytes. A mechanisticstudy demonstrated that JNK and p38 MAPK pathways are involved in IL-12/23p40 overproductionin purified TNFRp55-/- DCs as well as in the JAWS II cell line. This deregulationwas once again attributed to TNFRp55 deficiency since CAY10500, a specific inhibitor ofthis pathway, compromised TNF-mediated IL-12/23p40 control in LPS-stimulated WTDCs. Simultaneously, this inhibition reduced IL-10 production, suggesting its role mediatingIL-12/23p40 regulation by TNFRp55 pathway. These results provide experimentaldata on the existence of a TNFRp55-mediated anti-inflammatory circuit in DCs. Moreover,these cells may be considered as a novel target in the treatment of ReA.