Critical Role of IRF-5 in the Development of T helper 1 responses to Leishmania donovani infection

Abstract

The transcription factor Interferon Regulatory Factor 5 (IRF-5) has been shown to be involved in the induction of proinflammatory cytokines in response to viral infections and TLR activation and to play an essential role in the innate inflammatory response. In this study, we used the experimental model of visceral leishmaniasis to investigate the role of IRF-5 in the generation of Th1 responses and in the formation of Th1-type liver granulomas in Leishmania donovani infected mice. We show that TLR7-mediated activation of IRF-5 is essential for the development of Th1 responses to L. donovani in the spleen during chronic infection. We also demonstrate that IRF-5 deficiency leads to the incapacity to control L. donovani infection in the liver and to the formation of smaller granulomas. Granulomas in Irf5-/- mice are characterized by an increased IL-4 and IL-10 response and concomitant low iNOS expression. Collectively, these results identify IRF-5 as a critical molecular switch for the development of Th1 immune responses following L. donovani infections and reveal an indirect role of IRF-5 in the regulation of iNOS expression.

Akt2 Deficiency Protects from Acute Lung Injury via Alternative Macrophage Activation and miR-146a Induction in Mice

“…In acid aspiration lung injury, TLR4/TRIF/TRAF6 signaling in lung macrophages was shown to determine the susceptibility to ARDS in vivo (12,33). Both TRAF6 and IRF5 lead to NF-kB activation, but IRF5 is also an important regulator of iNOS and IL-12b expression and, thus, M1 polarization (23,52,(57)(58)(59)(60). We found that WT macrophages upregulate TRAF6 and IRF5 gene expression in line with their M1 phenotype, whereas Akt2-deficient macrophages, having an M2 phenotype, exhibit reduced levels of these factors both at baseline and upon acid injury.…”

Analysis of the expression of toll-like receptors 2 and 4 and cytokine production during experimental Leishmania chagasi infection

“…In addition to the involvement of TLR2 and 4 in leishmaniasis, other TLRs, such as TLR3, TLR7 and TLR9, also operate in Leishmania recognition (Flandin et al 2006, Schleicher et al 2007, Paun et al 2011. It was observed that TLR9 activation by Leishmania seems to be crucial in modulating the production of cytokines, such as IL-12 (Schleicher et al 2007).…”

Marginal Zone B Cells Regulate Antigen-Specific T Cell Responses during Infection

“…followed by isolation of CD11c + dendritic cells (DCs) using anti-CD11c beads (Miltenyi Biotec) as previously described (29). RNA was extracted using RNeasy mini kit (Qiagen) as per manufacturer's instruction.…”

“…Real-time PCR analysis was performed on cDNA using iQ SYBR Green supermix kit (Bio-Rad). IL-12p35, IL-12/IL-23 p40, and actin were amplified using primers described previously (29). All PCRs were carried out with an iCycler (Bio-Rad).…”