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Review
. 2017 Feb:44:14-19.
doi: 10.1016/j.coi.2016.10.005. Epub 2016 Nov 12.

Early innate immune responses to bacterial LPS

Charles V Rosadini  1 , Jonathan C Kagan  2
Affiliations
Review

Early innate immune responses to bacterial LPS

Charles V Rosadini et al. Curr Opin Immunol. 2017 Feb.

Abstract

A mammalian receptor for bacterial lipopolysaccharide (LPS), Toll-like receptor 4 (TLR4), plays a beneficial role in controlling bacterial infections, but is also a main driver of aberrant inflammation in lethal sepsis. As a result, investigation of TLR4 signaling has been a major area of research. Despite this focus, our understanding of the mechanisms that regulate TLR4 activities remains primitive. Nowhere is our knowledge of TLR4 biology more lacking than at the receptor-proximal level, where many factors act in concert to regulate LPS signaling. Several recent studies have begun filling these gaps in our knowledge. In this review, we discuss the importance of these receptor proximal activities in the spatiotemporal regulation of TLR4 signaling, and suggest interesting areas for future research.

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Figures

Figure 1
Figure 1
Receptor proximal activities control TLR4 signaling. (A) Extracellular factors regulate TLR4 trafficking into the endosomal compartment. LBP facilitates CD14-dependent delivery of LPS to TLR4/MD2 complexes. MD2 then promotes dimerization of TLR4/MD2/LPS complexes allowing for signaling from the plasma membrane and selection of TLR4 as a cargo for CD14-dependent endocytosis and subsequent TRIF-dependent signaling. CD13 inhibits TLR4 endocytosis and TRIF signaling but does not inhibit myddosome responses. In DCs, CD11b participates in driving TLR4 endocytosis and works within the endosome to promote TRIF signaling. In macrophages CD11b inhibits TLR4 responses by promoting degradation of MyD88 and TRIF. (B) Receptor-proximal factors modulate PIs to control TLR4 signaling. Sorting adaptors TIRAP and TRAM are prepositioned at membranes by interactions with PIs where they engage receptor ligand complexes for signaling. CD14 can modulate TIRAP association with the membrane. LPS binding promotes CD14 aggregation and PIP5K-dependent conversion of PI(4)P to PI(4,5)P2 resulting in increased TIRAP binding and myddosome signaling. Conversely, CD300b drives PI3K activation and conversion of PI(4,5)P2 to PI(3,4,5)P3 resulting in dissociation of TIRAP and MyD88 from the membrane. By doing so, CD300b promotes receptor trafficking and TRIF signaling.
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