CD14 controls the LPS-induced endocytosis of Toll-like Receptor 4

By I. Zanoni, Renato Ostuni, Lorri R. Marek, S. Barresi, Roman Barbalat, G. Barton, Fancesca Granucci, Jonathan C. Kagan. Cell, 2011

948 citations recorded by the source corpus.

The transport of Toll-like Receptors (TLRs) to various organelles has emerged as an essential means by which innate immunity is regulated. While most of our knowledge is restricted to regulators that promote the transport of newly synthesized receptors, the regulators that control TLR transport after microbial detection remain unknown. Here, we report that the plasma membrane localized Pattern Recognition Receptor (PRR) CD14 is required for the microbe-induced endocytosis of TLR4. In dendritic cells, this CD14-dependent endocytosis pathway is upregulated upon exposure to inflammatory mediators. We identify the tyrosine kinase Syk and its downstream effector PLCγ2 as important regulators of TLR4 endocytosis and signaling. These data establish that upon microbial detection, an upstream PRR (CD14) controls the trafficking and signaling functions of a downstream PRR (TLR4). This innate immune trafficking cascade illustrates how pathogen detection systems operate to induce both membrane transport and signal transduction.

Subfields: Immunology

View Paper: https://www.semanticscholar.org/paper/1b9e18e7d074b47d57a2374293898284a9d39974

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Citations in the corpus

• Overview of General and Discriminating Markers of Differential Microglia Phenotypes (2020, background): “…ionized calcium-binding adapter molecule 1 (IBA1; Yun et al., 2018), cluster of differentiation receptors (CD68, CD11b, CD14, CD45, CD80, and CD115; Zanoni et al., 2011; Fadini et al., 2013; Jenkins et al., 2013; Jeong et al., 2013; Rice et al., 2017), fractalkine receptor (CX3CR1; Jones et al.,…”
• Toll-Like Receptor Signaling Pathways (2014, background): “It induces ITAM-mediated Syk- and PLCγ2-dependent endocytosis to promote TLR4 internalization into endosomes for activation of TRIF-dependent signaling (65).”
• High‐Dimensional Single‐Cell Mapping of Central Nervous System Immune Cells Reveals Distinct Myeloid Subsets in Health, Aging, and Disease (2018, neutral): “, 2009) and upregulated by inflammatory cytokines like TNF-a (Zanoni et al., 2011).”
• Innate Immune Pattern Recognition: A Cell Biological Perspective (2015, neutral): “TLR4 signaling and adaptor engagement is sequential, starting at the plasma membrane with CD14-dependent movement of LPS to TLR4 and the initiation of TIRAP/MyD88 signaling, followed by CD14-dependent receptor movement and TRAM/TRIF signaling from endosomes (67).”
• Gut microbiota, intestinal permeability, and systemic inflammation: a narrative review (2023, background): “LPS recognition by TLR4 is helped by LPS-binding protein (LBP) and CD14, with an indispensable contribution of the MD-2 protein stably associated with the extracellular fragment of the receptor [23].”