Department of Veterinary Medicine

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Author: search.filters.author.Fu, Yong

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    IL-27 Negatively Regulates Tip-DC Development during Infection
    (American Society for Microbiology, 2021-02-16) Liu, Gongguan; Abas, Osama; Fu, Yong; Chen, Yanli; Strickland, Ashley B.; Sun, Donglei; Shi, Meiqing
    Tumor necrosis factor (TNF)/inducible nitric oxide synthase (iNOS)-producing dendritic cells (Tip-DCs) have profound impacts on host immune responses during infections. The mechanisms regulating Tip-DC development remain largely unknown. Here, using a mouse model of infection with African trypanosomes, we show that a deficiency in interleukin-27 receptor (IL-27R) signaling results in escalated intrahepatic accumulation of Ly6C-positive (Ly6C1) monocytes and their differentiation into Tip-DCs. Blocking Tip-DC development significantly ameliorates liver injury and increases the survival of infected IL-27R2/2 mice. Mechanistically, Ly6C1 monocyte differentiation into pathogenic Tip-DCs in infected IL-27R2/2 mice is driven by a CD41 T cell-interferon gamma (IFN-g) axis via cell-intrinsic IFN-g signaling. In parallel, hyperactive IFN-g signaling induces cell death of Ly6C-negative (Ly6C2) monocytes in a cell-intrinsic manner, which in turn aggravates the development of pathogenic Tip-DCs due to the loss of the negative regulation of Ly6C2 monocytes on Ly6C1 monocyte differentiation into Tip-DCs. Thus, IL-27 inhibits the dual-track exacerbation of Tip-DC development induced by a CD41 T cell–IFN-g axis. We conclude that IL-27 negatively regulates Tip-DC development by preventing the cell-intrinsic effects of IFN-g and that the regulation involves CD41 T cells and Ly6C2 monocytes. Targeting IL-27 signaling may manipulate Tip-DC development for therapeutic intervention.
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    VCAM1/VLA4 interaction mediates Ly6Clow monocyte recruitment to the brain in a TNFR signaling dependent manner during fungal infection
    (PLoS, 2020-02-26) Sun, Donglei; Zhang, Mingshun; Sun, Peng; Liu, Gongguan; Strickland, Ashley B.; Chen, Yanli; Fu, Yong; Yosri, Mohammed; Shi, Meiqing
    Monocytes exist in two major populations, termed Ly6C^hi and Ly6C^low monocytes. Compared to Ly6C^hi monocytes, less is known about Ly6C^low monocyte recruitment and mechanisms involved in the recruitment of this subset. Furthermore, the role of Ly6C^low monocytes during infections is largely unknown. Here, using intravital microscopy, we demonstrate that Ly6C^low monocytes are predominantly recruited to the brain vasculature following intravenous infection with Cryptococcus neoformans, a fungal pathogen causing meningoencephalitis. The recruitment depends primarily on the interaction of VCAM1 expressed on the brain endothelium with VLA4 expressed on Ly6C^low monocytes. Furthermore, TNFR signaling is essential for the recruitment through enhancing VLA4 expression on Ly6C^low monocytes. Interestingly, the recruited Ly6C^low monocytes internalized C. neoformans and carried the organism while crawling on and adhering to the luminal wall of brain vasculature and migrating to the brain parenchyma. Our study reveals a substantial recruitment of Ly6C^low monocytes to the brain and highlights important properties of this subset during infection.
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    Fungal dissemination is limited by liver macrophage filtration of the blood
    (Springer Nature, 2019-10-08) Sun, Donglei; Sun, Peng; Li, Hongmei; Zhang, Mingshun; Liu, Gongguan; Strickland, Ashley B.; Chen, Yanli; Fu, Yong; Xu, Juan; Yosri, Mohammed; Nan, Yuchen; Zhou, Hong; Zhang, Xiquan; Shi, Meiqing
    Fungal dissemination into the bloodstream is a critical step leading to invasive fungal infections. Here, using intravital imaging, we show that Kupffer cells (KCs) in the liver have a prominent function in the capture of circulating Cryptococcus neoformans and Candida albicans, thereby reducing fungal dissemination to target organs. Complement C3 but not C5, and complement receptor CRIg but not CR3, are involved in capture of C. neoformans. Internalization of C. neoformans by KCs is subsequently mediated by multiple receptors, including CR3, CRIg, and scavenger receptors, which work synergistically along with C5aR signaling. Following phagocytosis, the growth of C. neoformans is inhibited by KCs in an IFN-γ independent manner. Thus, the liver filters disseminating fungi from circulation via KCs, providing a mechanistic explanation for the enhanced risk of cryptococcosis among individuals with liver diseases, and suggesting a therapeutic strategy to prevent fungal dissemination through enhancing KC functions.