IL-4Rα-Independent Expression of Mannose Receptor and Ym1 by Macrophages Depends on their IL-10 Responsiveness

IL-4Rα-dependent responses are essential for granuloma formation and host survival during acute schistosomiasis. Previously, we demonstrated that mice deficient for macrophage-specific IL-4Rα (LysMcreIl4ra−/lox) developed increased hepatotoxicity and gut inflammation; whereas inflammation was restricted to the liver of mice lacking T cell-specific IL-4Rα expression (iLckcreIl4ra−/lox). In the study presented here we further investigated their role in liver granulomatous inflammation. Frequencies and numbers of macrophage, lymphocyte or granulocyte populations, as well as Th1/Th2 cytokine responses were similar in Schistosoma mansoni-infected LysMcreIl4ra−/lox liver granulomas, when compared to Il4ra−/lox control mice. In contrast, a shift to Th1 responses with high IFN-γ and low IL-4, IL-10 and IL-13 was observed in the severely disrupted granulomas of iLckcreIl4ra−/lox and Il4ra−/− mice. As expected, alternative macrophage activation was reduced in both LysMcreIl4ra−/lox and iLckcreIl4ra−/lox granulomas with low arginase 1 and heightened nitric oxide synthase RNA expression in granuloma macrophages of both mouse strains. Interestingly, a discrete subpopulation of SSChighCD11b+I-A/I-EhighCD204+ macrophages retained expression of mannose receptor (MMR) and Ym1 in LysMcreIl4ra−/lox but not in iLckcreIl4ra−/lox granulomas. While aaMφ were in close proximity to the parasite eggs in Il4ra−/lox control mice, MMR+Ym1+ macrophages in LysMcreIl4ra−/lox mice were restricted to the periphery of the granuloma, indicating that they might have different functions. In vivo IL-10 neutralisation resulted in the disappearance of MMR+Ym1+ macrophages in LysMcreIl4ra−/lox mice. Together, these results show that IL-4Rα-responsive T cells are essential to drive alternative macrophage activation and to control granulomatous inflammation in the liver. The data further suggest that in the absence of macrophage-specific IL-4Rα signalling, IL-10 is able to drive mannose receptor- and Ym1-positive macrophages, associated with control of hepatic granulomatous inflammation

Dendritic Cells in Chronic Mycobacterial Granulomas Restrict Local Anti-Bacterial T Cell Response in a Murine Model

Background: Mycobacterium-induced granulomas are the interface between bacteria and host immune response. During acute infection dendritic cells (DCs) are critical for mycobacterial dissemination and activation of protective T cells. However, their role during chronic infection in the granuloma is poorly understood. Methodology/Principal Findings: We report that an inflammatory subset of murine DCs are present in granulomas induced by Mycobacteria bovis strain Bacillus Calmette-guerin (BCG), and both their location in granulomas and costimulatory molecule expression changes throughout infection. By flow cytometric analysis, we found that CD11c + cells in chronic granulomas had lower expression of MHCII and co-stimulatory molecules CD40, CD80 and CD86, and higher expression of inhibitory molecules PD-L1 and PD-L2 compared to CD11c + cells from acute granulomas. As a consequence of their phenotype, CD11c + cells from chronic lesions were unable to support the reactivation of newly-recruited, antigen 85Bspecific CD4 + IFNc + T cells or induce an IFNc response from naïve T cells in vivo and ex vivo. The mechanism of this inhibition involves the PD-1:PD-L signaling pathway, as ex vivo blockade of PD-L1 and PD-L2 restored the ability of isolated CD11c + cells from chronic lesions to stimulate a protective IFNc T cell response. Conclusions/Significance: Our data suggest that DCs in chronic lesions may facilitate latent infection by down-regulating protective T cell responses, ultimately acting as a shield that promotes mycobacterium survival. This DC shield may explai

Sex- And tissue-specific effects of binge-level prenatal alcohol consumption on DNA methylation at birth

Background: Binge-level prenatal alcohol exposure (PAE) causes developmental abnormalities, which may be mediated in part by epigenetic mechanisms. Despite this, few studies have characterised the association of binge PAE with DNA methylation in offspring. Methods: We investigated the association between binge PAE and genome-wide DNA methylation profiles in a sex-specific manner in neonatal buccal and placental samples. Results: We identified no differentially methylated CpGs or differentially methylated regions (DMRs) at false discovery rate&nbsp;&lt;0.05. However, using a sum-of-ranks approach, we identified a DMR in each tissue of female offspring. The DMR identified in buccal samples is located near regions with previously-reported associations to fetal alcohol spectrum disorder (FASD) and binge PAE. Conclusion: Our findings warrant further replication and highlight a potential epigenetic link between binge PAE and FASD. </jats:p

Relationships between the usage of televisions, computers, and mobile phones and the quality of sleep in a Chinese population : community-based cross-sectional study

202010 bcmaVersion of RecordPublishe

Efficacy and feasibility of a 12-week Tai Chi training for the prophylaxis of episodic migraine in Hong Kong Chinese women : a randomized controlled trial

202311 bckwVersion of RecordOthersHong Kong Polytechnic UniversityPublishe