6% of the total splenocyte population 48 h after infection of WT mice, and displayed upregulated CD80, CD86, CD40, and MHC class II expression as well as a DC morphology. Serbina et al. [6] further showed

that the production of TNF-α and NO was markedly reduced in CCR2−/− mice, an observation in-line with the high susceptibility of these mice to Listeria mono-cytogenes infection, whereas CD8+ and CD4+ T-cell responses were preserved. The identified monocyte-derived DCs were named TIP (TNF-iNOS producing) DCs, and were shown to GS-1101 order play a crucial role in early antimicrobial defense, with their recruitment requiring CCR2 [6]. Of note, these TIP-DCs were not directly infected with Listeria monocytogenes and therefore are probably not involved in bacterial transport to the spleen [6]. Interestingly, in another study, the resistance to Leishmania major infection (in C57BL/6 mice) was associated with the presence of iNOS-producing inflammatory DCs that depend 3-deazaneplanocin A in vitro on a Th1 microenvironment, that is, IFN-γ-producing CD4+ T cells. By contrast, STAT-6-deficient BALB/c mice, which are defective in IL-4 and IL-13 signaling, displayed

higher recruitment of iNOS-DC in LN following Leishmania major infection [8]. Similarly, inflammatory DCs were shown to be the main iNOS-producing cells in the spleen and peritoneal cavity of mice infected with Brucella melitensis and their activation required TLR4- or TLR9-mediated MYD88-dependent triggering [9] (Fig. 2). Although these inflammatory DCs have been shown to play a beneficial role in intracellular pathogen clearance, they may also Avelestat (AZD9668) mediate immune

pathology during parasitic infection [11]. In Trypanosoma brucei brucei infected mice, bone marrow derived monocytes were found to be recruited to the spleen, LNs, and liver where they differentiated into mature inflammatory DCs and represented a major cellular source of TNF and iNOS. Infected IL-10 KO mice had a higher proportion of inflammatory DCs but this increased population was associated with enhanced liver injury and early death of the host. Collectively, these observations [8, 11] show that Th1-type cytokines favor the differentiation of inflammatory DCs at the site of infection, whereas IL-10, IL-4, and IL-13 act as negative regulators. Monocyte emigration from the bone marrow in steady state conditions and during Listeria monocytogenes infection has been shown to be dependent on CCR2 signaling, but CCR2 appears not to be required for migration from the blood to the tissues [12]. Thus, in CCR2−/− mice, monocytes are retained in the bone marrow and resemble the inflammatory DCs that are normally recruited to the spleens of WT mice infected with Listeria monocytogenes.