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Sterile particle-induced inflammation is mediated by macrophages releasing IL-33 through a Bruton's tyrosine kinase-dependent pathway.

ABSTRACT: Initiation of the innate sterile inflammatory response that can develop in response to microparticle exposure is little understood. Here, we report that a potent type?2 immune response associated with the accumulation of neutrophils, eosinophils and alternatively activated (M2) macrophages was observed in response to sterile microparticles similar in size to wear debris associated with prosthetic implants. Although elevations in interleukin-33 (IL-33) and type?2 cytokines occurred independently of caspase-1 inflammasome signalling, the response was dependent on Bruton's tyrosine kinase (BTK). IL-33 was produced by macrophages and BTK-dependent expression of IL-33 by macrophages was sufficient to initiate the type?2 response. Analysis of inflammation in patient periprosthetic tissue also revealed type?2 responses under aseptic conditions in patients undergoing revision surgery. These findings indicate that microparticle-induced sterile inflammation is initiated by macrophages activated to produce IL-33. They further suggest that both BTK and IL-33 may provide therapeutic targets for wear debris-induced periprosthetic inflammation.

SUBMITTER: Mishra PK

PROVIDER: S-EPMC6581031 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Sterile particle-induced inflammation is mediated by macrophages releasing IL-33 through a Bruton's tyrosine kinase-dependent pathway.

Mishra Pankaj K PK Palma Mark M Buechel Bonnie B Moore Jeffrey J Davra Viralkumar V Chu Niansheng N Millman Ariel A Hallab Nadim J NJ Kanneganti Thirumala-Devi TD Birge Raymond B RB Behrens Edward M EM Rivera Amariliz A Beebe Kathleen S KS Benevenia Joseph J Gause William C WC

Nature materials 20190121 3

Initiation of the innate sterile inflammatory response that can develop in response to microparticle exposure is little understood. Here, we report that a potent type 2 immune response associated with the accumulation of neutrophils, eosinophils and alternatively activated (M2) macrophages was observed in response to sterile microparticles similar in size to wear debris associated with prosthetic implants. Although elevations in interleukin-33 (IL-33) and type 2 cytokines occurred independently ...[more]

PMID: 30664693

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Project description:BACKGROUND & AIMS:Neutrophils and liver sinusoidal endothelial cells (LSECs) both contribute to sterile inflammatory injury during ischemia/reperfusion (I/R), a well-known liver surgical stress. Interleukin-33 (IL-33) has been shown to drive neutrophil infiltration during inflammatory responses through its receptor ST2. We recently reported that infiltrating neutrophils form neutrophil extracellular traps (NETs), which exacerbate sterile inflammatory injury in liver I/R. Here, we sought to determine the role of IL-33 in NET formation during liver sterile inflammation. METHODS:Evaluation of IL-33 forming NETs was investigated using a partial liver I/R model to generate sterile injury in healthy WT, IL-33 and ST2 knockouts. Serum levels of IL-33 and myeloperoxidase (MPO)-DNA complex were measured in both humans and mice after the first surgery. Liver damage was assessed. Mouse neutrophil depletion was performed by intraperitoneal injection of anti-Ly6G antibody before I/R. RESULTS:Patients undergoing liver resection showed a significant increase in serum IL-33 compared to healthy volunteers. This coincided with higher serum MPO-DNA complexes. NET formation was decreased in IL-33 and ST2 knockout mice compared with control mice, after liver I/R. IL-33 or ST2 deficiency protected livers from I/R injury, whereas rIL-33 administration during I/R exacerbated hepatotoxicity and systemic inflammation. In vitro, IL-33 is released from LSECs to promote NET formation. IL-33 deficient LSECs failed to induce NETs. ST2 deficient neutrophils limited their capacity to form NETs in vitro and adoptive transfer of ST2 knockout neutrophils to neutrophil-depleted WT mice significantly decreased NET formation. CONCLUSIONS:Data establish that IL-33, mainly released from LSECs, causes excessive sterile inflammation after hepatic I/R by inducing NET formation. Therapeutic targeting of IL-33/ST2 might extend novel strategies to minimize organ damage in various clinical settings associated with sterile inflammation. LAY SUMMARY:Liver ischemia and reperfusion injury results in the formation of neutrophil extracellular traps, which contribute to organ damage in liver surgeries. Herein, we show that IL-33 is released from liver sinusoidal endothelial cells to promote NET formation during liver I/R, which exacerbates inflammatory cascades and sterile inflammation.

Dataset Information

Sterile particle-induced inflammation is mediated by macrophages releasing IL-33 through a Bruton's tyrosine kinase-dependent pathway.

Publications

Sterile particle-induced inflammation is mediated by macrophages releasing IL-33 through a Bruton's tyrosine kinase-dependent pathway.

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