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

Abstract

Dendritic cells (DCs) play critical functions in the initiation of immune responses. Understanding their role in reactive arthritis (ReA) will help delineate the pathogenesis of this arthropathy. In early studies, we detected IL-12/23p40 deregulation in Yersinia entercolitica (Ye)-induced ReA in TNFRp55-deficient (TNFRp55-/-) mice. In this study, we assessed 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)-stimulated TNFRp55-/-splenocytes obtained on arthritis onset (day 14 after Ye infection). Later, DCs were identified as a precise source of IL-12/23p40 since increased frequency of splenic IL-12/23p40+DCs was detected in TNFRp55-/- mice. After robust in vivo amplification of DCs by injection of Fms-like tyrosine kinase 3-Ligand (Flt3L)-transfected BL16 melanoma, DCs were purified. These cells recapitulated the higher production of IL-12/23p40 under TNFRp55deficiency. In agreement with these results, TNFRp55-/- DCs promoted Th1 and Th17 programs by co-culture with WT CD4+lymphocytes. A mechanistic study demonstrated that JNK and p38 MAPK pathways are involved in IL-12/23p40 overproduction in purified TNFRp55-/- DCs as well as in the JAWS II cell line. This deregulation was once again attributed to TNFRp55 deficiency since CAY10500, a specific inhibitor of this pathway, compromised TNF-mediated IL-12/23p40 control in LPS-stimulated WT DCs. Simultaneously, this inhibition reduced IL-10 production, suggesting its role mediating IL-12/23p40 regulation by TNFRp55 pathway. These results provide experimental data 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.

The Yersinia Phage X1 Administered Orally Efficiently Protects a Murine Chronic Enteritis Model Against Yersinia enterocolitica Infection

“…The level of proinflammatory cytokines in the Bacteria-Phage group was significantly decreased compared with the PBS-treated group (P < 0.05). Nevertheless, the level of TNF-α in the spleen of the treatment group was still high at 72 h. A number of studies have shown that TNF-α also has an anti-inflammatory effect in limiting inflammation in vivo and autoimmune diseases (Mayordomo et al, 2018).…”

TLR4-dependent effects of ISAg treatment on conventional T cell polarization in vivo

“…Since it is well established that the overproduction of IL12p40 by DCs leads to Th1 polarization of conventional CD4 + and CD8 + T cells (Mayordomo et al. 2018), we examined whether repeated oral administration of ISAg could induce IL12 production and the maturation of APCs such as DCs and macrophages. For this purpose, we used Yet40 (IL12p40 reporter) mice (Reinhardt et al.…”

Reactive arthritis – an interdisciplinary issue

“…Interleukin 17 is confirmed to be present in synovial fluid of ReA-patients. Toll-like receptor 4 (TLR 4) responsible for recognizing lipopolysaccharides of Gram-negative bacteria exerts an influence on the inflammation [20,21].…”

“…Interleukinę 17 stwierdza się w płynie stawowym pacjentów z ReA. Na rozwój zapalenia wpływają receptory toll-like 4 (TLR 4) odpowiedzialne za rozpoznawanie liposacharydów bakterii Gram-ujemnych [20,21].…”