Hemorrhagic shock primes for IL-1β processing: role of upregulated TLR2 (136.1)

Abstract

Abstract IL-1β contributes to post-trauma sepsis, and its release requires processing in inflammasomes. Hemorrhagic shock (HS) primes for IL-1β release in response to LPS via yet unclear mechanisms. We have reported that HS-activated neutrophils (PMN) augment LPS/TLR4 signaling upregulation of TLR2 in alveolar macrophages (AM), thereby sensitizing the AM to TLR2 ligands. Here, we addressed the role of upregulated TLR2 in the HS-primed IL-1β processing. WT, TLR4-mutant and TLR2 KO mice were subjected to HS, followed by intratracheal LPS (30 µg/kg B.W.) and PGN (30 µg/kg B.W.) at 2h and 4h after HS, respectively. Bronchoalveolar lavage fluids (BALF) were collected at 2 h after PGN for detection of IL-1β. In vitro, AM were co-cultured with PMN isolated from HS mice, and treated with LPS, PMN was then removed and PGN was added at 2h. IL-1β and caspase-1 maturation in the AM were assessed. In vivo treatments of LPS and PGN caused a marked increase in IL-1β in BALF in the WT/HS mice, but not in the WT/sham, TLR4-mutant/HS or TLR2 KO/HS mice. HS-activated PMN increased TLR2 expression in AM in response to LPS, and subsequently increased caspase-1 and IL-1β maturation in the AM as well as IL-1β release in response to PGN. Moreover increasing extracellular [K+] failed to prevent the TLR2 signal-induced IL-1β maturation. In HS, amplified TLR2 signaling acts as a second signal in stimulating caspase-1 and IL-1β maturation via mechanisms independent of K+ efflux.