TLRs are a class of pattern recognition receptors (PRRs) that detect invading microbes by recognizing pathogen-associated molecular patterns (PAMPs). Upon PAMP engagement, TLRs activate a signaling cascade that leads to the production of inflammatory mediators. The localization of TLRs, either on the plasma membrane or in the endolysosomal compartment, has been considered to be a fundamental aspect to determine to which ligands the receptors bind, and which transduction pathways are induced. However, new observations have challenged this view by identifying complex trafficking events that occur upon TLR-ligand binding. These findings have highlighted the central role that endocytosis and receptor trafficking play in the regulation of the innate immune response. Here, we review the TLR4 and TLR9 transduction pathways and the importance of their different subcellular localization during the inflammatory response. Finally, we discuss the implications of TLR9 subcellular localization in autoimmunity.
A proper regulation of the innate immune response is fundamental to keep the immune system in check and avoid a chronic status of inflammation. As they act as negative modulators of TLR signaling pathways, miRNAs have been recently involved in the control of the inflammatory response. However, their role in the context of endotoxin tolerance is just beginning to be explored. We here show that miR-146b is upregulated in human monocytes tolerized by LPS, IL-10, or TGFβ priming and demonstrate that its transcription is driven by STAT3 and RUNX3, key factors downstream of IL-10 and TGFβ signaling. Our study also found that IFNγ, known to revert LPS tolerant state, inhibits miR-146b expression. Finally, we provide evidence that miR-146b levels have a profound effect on the tolerant state, thus candidating miR-146b as a molecular mediator of endotoxin tolerance.
Vaccines represent the discovery of utmost importance for global health, due to both prophylactic action to prevent infections and therapeutic intervention in neoplastic diseases. Despite this, current vaccination strategies need to be refined to successfully generate robust protective antigen-specific memory immune responses. To address this issue, one possibility is to exploit the high efficiency of dendritic cells (DCs) as antigen-presenting cells for T cell priming. DCs functional plasticity allows shaping the outcome of immune responses to achieve the required type of immunity. Therefore, the choice of adjuvants to guide and sustain DCs maturation, the design of multifaceted vehicles, and the choice of surface molecules to specifically target DCs represent the key issues currently explored in both preclinical and clinical settings. Here, we review advances in DCs-based vaccination approaches, which exploit direct in vivo DCs targeting and activation options. We also discuss the recent findings for efficient antitumor DCs-based vaccinations and combination strategies to reduce the immune tolerance promoted by the tumor microenvironment.
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