Toll-like Receptors Activate Innate and Adaptive Immunity by using Dendritic Cell-Intrinsic and -Extrinsic Mechanisms

Department of Microbiology & Immunology, University of California, San Francisco, CA, 94143, USA.
Immunity (Impact Factor: 21.56). 08/2008; 29(2):272-82. DOI: 10.1016/j.immuni.2008.05.016
Source: PubMed


Toll-like receptors (TLRs) play prominent roles in initiating immune responses to infection, but their roles in particular cell types in vivo are not established. Here we report the generation of mice selectively lacking the crucial TLR-signaling adaptor MyD88 in dendritic cells (DCs). In these mice, the early production of inflammatory cytokines, especially IL-12, was substantially reduced after TLR stimulation. Whereas the innate interferon-gamma response of natural killer cells and of natural killer T cells and the Th1 polarization of antigen-specific CD4(+) T cells were severely compromised after treatment with a soluble TLR9 ligand, they were largely intact after administration of an aggregated TLR9 ligand. These results demonstrate that the physical form of a TLR ligand affects which cells can respond to it and that DCs and other innate immune cells can respond via TLRs and collaborate in promoting Th1 adaptive immune responses to an aggregated stimulus.

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Available from: Baidong Hou, Oct 10, 2015
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    • "Therefore, TLR7/TLR9 signaling can also affect pathology in a Type-I IFN independent manner. DCs that lacked the TLR-adaptor protein MyD88 showed an overall decrease in the levels of inflammatory cytokines in the spleen after TLR9 stimulation with CpG [36], [51]. Furthermore, TLR signaling by DCs also affects B cell function as MyD88 deficient DCs had significantly lower levels of IgG2a anti-nucleosome autoAbs [52]. "
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    PLoS ONE 08/2014; 9(8):e102151. DOI:10.1371/journal.pone.0102151 · 3.23 Impact Factor
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    • "Fu (National University of Singapore, Singapore; Kano et al., 2003). MyD88 flox mice were provided by A. DeFranco (University of California, San Francisco, CA; Hou et al., 2008). All these transgenic mice used backcrossed 10 times to C57/BL6 background. "
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    ABSTRACT: Low-grade systemic inflammation is often associated with metabolic syndrome, which plays a critical role in the development of the obesity-associated inflammatory diseases, including insulin resistance and atherosclerosis. Here, we investigate how Toll-like receptor-MyD88 signaling in myeloid and endothelial cells coordinately participates in the initiation and progression of high fat diet-induced systemic inflammation and metabolic inflammatory diseases. MyD88 deficiency in myeloid cells inhibits macrophage recruitment to adipose tissue and their switch to an M1-like phenotype. This is accompanied by substantially reduced diet-induced systemic inflammation, insulin resistance, and atherosclerosis. MyD88 deficiency in endothelial cells results in a moderate reduction in diet-induced adipose macrophage infiltration and M1 polarization, selective insulin sensitivity in adipose tissue, and amelioration of spontaneous atherosclerosis. Both in vivo and ex vivo studies suggest that MyD88-dependent GM-CSF production from the endothelial cells might play a critical role in the initiation of obesity-associated inflammation and development of atherosclerosis by priming the monocytes in the adipose and arterial tissues to differentiate into M1-like inflammatory macrophages. Collectively, these results implicate a critical MyD88-dependent interplay between myeloid and endothelial cells in the initiation and progression of obesity-associated inflammatory diseases.
    Journal of Experimental Medicine 04/2014; 211(5). DOI:10.1084/jem.20131314 · 12.52 Impact Factor
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    • "Cathepsin S, a regulator of intracellular trafficking of MHC class II molecules in DCs (Iwasaki & Medzhitov, 2004), was also upregulated (Table 1). Induced TNFa (1.95-fold) and IFNc (11.19-fold) transcripts could also be seen as playing a role in promoting DC maturation (Nakagawa & Rudensky, 1999; Fujii et al., 2004; Hou et al., 2008). We found that the triggering receptor expressed on myeloid cells 1 (TREM1) signaling pathway was significantly represented (Fig. 1) with several upregulated transcripts (Table 1). "
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