Synergy Between 15-lipoxygenase and Secreted PLA Promotes Inflammation by Formation of TLR4 Agonists from Extracellular Vesicles

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2020 Sep 25

PMID 32973091

Citations 8

Authors

Van Thai Ha

Dusko Lainscek

Bernd Gesslbauer

Eva Jarc-Jovicic

Tuulia Hyotylainen

Nejc Ilc

Katja Lakota

Matija Tomsic

Fons A J van de Loo

Valery Bochkov

Toni Petan

Roman Jerala

Mateja Mancek-Keber

Affiliations

Soon will be listed here.

Abstract

Damage-associated endogenous molecules induce innate immune response, thus making sterile inflammation medically relevant. Stress-derived extracellular vesicles (stressEVs) released during oxidative stress conditions were previously found to activate Toll-like receptor 4 (TLR4), resulting in expression of a different pattern of immune response proteins in comparison to lipopolysaccharide (LPS), underlying the differences between pathogen-induced and sterile inflammation. Here we report that synergistic activities of 15-lipoxygenase (15-LO) and secreted phospholipase A (sPLA) are needed for the formation of TLR4 agonists, which were identified as lysophospholipids (lysoPLs) with oxidized unsaturated acyl chain. Hydroxy, hydroperoxy, and keto products of 2-arachidonoyl-lysoPI oxidation by 15-LO were identified by mass spectrometry (MS), and they activated the same gene pattern as stressEVs. Extracellular PLA activity was detected in the synovial fluid from rheumatoid arthritis and gout patients. Furthermore, injection of sPLA promoted K/BxN serum-induced arthritis in mice, whereby ankle swelling was partially TLR4 dependent. Results confirm the role of oxidized lysoPL of stressEVs in sterile inflammation that promotes chronic diseases. Both 15-LO and sPLA enzymes are induced during inflammation, which opens the opportunity for therapy without compromising innate immunity against pathogens.

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