A TLR4-independent critical role for CD14 in intracellular LPS sensing.

Swathy O Vasudevan, Ashley J Russo, Puja Kumari, Sivapriya Kailasan Vanaja, Vijay A Rathinam

Cell reports 2022 May 03

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Intracellular lipopolysaccharide (LPS) sensing by the noncanonical inflammasome comprising caspase-4 or -11 governs antibacterial host defense. How LPS gains intracellular access in vivo is largely unknown. Here, we show that CD14-an LPS-binding protein with a well-documented role in TLR4 activation-plays a vital role in intracellular LPS sensing in vivo. By generating Cd14-/- and Casp11-/- mice strains on a Tlr4-/- background, we dissociate CD14's known role in TLR4 signaling from its role in caspase-11 activation and show a TLR4-independent role for CD14 in GSDMD activation, pyroptosis, alarmin release, and the lethality driven by cytosolic LPS. Mechanistically, CD14 enables caspase-11 activation by mediating cytosolic localization of LPS in a TLR4-independent manner. Overall, our findings attribute a critical role for CD14 in noncanonical inflammasome sensing of LPS in vivo and establish-together with previous literature-CD14 as an essential proximal component of both TLR4-based extracellular and caspase-11-based intracellular LPS surveillance. Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.

Citation

Swathy O Vasudevan, Ashley J Russo, Puja Kumari, Sivapriya Kailasan Vanaja, Vijay A Rathinam. A TLR4-independent critical role for CD14 in intracellular LPS sensing. Cell reports. 2022 May 03;39(5):110755