CD36 ligands promote sterile inflammation through assembly of a Toll-like receptor 4 and 6 heterodimer

By C. Stewart, L. Stuart, K. Wilkinson, J. V. van Gils, Jiusheng Deng, A. Halle, K. Rayner, L. Boyer, Ruiqin Zhong, W. Frazier and 4 more. Nature Immunology, 2009

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In atherosclerosis and Alzheimer's disease, deposition of the altered self components oxidized low-density lipoprotein (LDL) and amyloid-β triggers a protracted sterile inflammatory response. Although chronic stimulation of the innate immune system is believed to underlie the pathology of these diseases, the molecular mechanisms of activation remain unclear. Here we show that oxidized LDL and amyloid-β trigger inflammatory signaling through a heterodimer of Toll-like receptors 4 and 6. Assembly of this newly identified heterodimer is regulated by signals from the scavenger receptor CD36, a common receptor for these disparate ligands. Our results identify CD36-TLR4-TLR6 activation as a common molecular mechanism by which atherogenic lipids and amyloid-β stimulate sterile inflammation and suggest a new model of TLR heterodimerization triggered by coreceptor signaling events.

Subfields: Immunology, Neurology, Surgery

View Paper: https://www.semanticscholar.org/paper/0330b71aab40b35fb7949b35ee2835a158cc3ffb

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Citations in the corpus

Atherosclerosis: current pathogenesis and therapeutic options (2011, background): “TLR4 and TLR6 cooperate with CD36 in this inflammatory response of macrophages to atherogenic lipids; that is, oxLDL sequestered by CD36 induces intracellular CD36-TLR4-TLR6 heteromerization, activating NF-κB and chemokine expressio”
Sterile inflammation: sensing and reacting to damage (2010, background): “Induction of NF-κB signalling through this co-receptor complex to produce IL-1β may serve as a priming event for subsequent NLRP3 activatio”
The role of microglia in amyloid clearance from the AD brain (2010, background): “The cell surface receptor complex of fAb is composite of class A scavenger receptor (SR-A), the class B scavenger receptors CD36, a6b1 integrin, CD14, CD47 and TLR2, TLR4, TLR6 and TLR9 (Bamberger et al. 2003; Paresce et al. 1996; Reed-Geaghan et al. 2009; Stewart et al. 2010).”
Neuroinflammation and M2 microglia: the good, the bad, and the inflamed (2014, background): “Amyloid β can bind to several innate immune receptors present on microglia, such as TRL2 [114], TRL4 [116], TLR6 [116], and CD14 [117], all of which can lead to activation when triggered.”
NLRP3 Inflammasome and the IL-1 Pathway in Atherosclerosis. (2018, background): “binding to macrophage CD36 induces the assembly of a TLR4/ TLR6 heterodimer, resulting in NF-κB signaling and priming of these cells for inflammasome activation.(24) Recently, oxLDL”
Low-density lipoproteins cause atherosclerotic cardiovascular disease: pathophysiological, genetic, and therapeutic insights: a consensus statement from the European Atherosclerosis Society Consensus Panel (2020, background): “NFjB-dependent expression of chemokines, such as CXCL1, resulting in further recruitment of monocytes.(139) Such leucocyte recruit-”