Inflammasome-Independent Leukotriene B4 Production Drives Crystalline Silica-Induced Sterile Inflammation.

Abstract

Silicosis is a lung inflammatory disease caused by chronic exposure to crystalline silica (CS). Leukotriene B4 (LTB4) plays an important role in neutrophilic inflammation, which drives silicosis and promotes lung cancer. In this study, we examined the mechanisms involved in CS-induced inflammatory pathways. Phagocytosis of CS particles is essential for the production of LTB4 and IL-1β in mouse macrophages, mast cells, and neutrophils. Phagosomes enclosing CS particles trigger the assembly of lipidosome in the cytoplasm, which is likely the primary source of CS-induced LTB4 production. Activation of the JNK pathway is essential for both CS-induced LTB4 and IL-1β production. Studies with bafilomycin-A1- and NLRP3-deficient mice revealed that LTB4 synthesis in the lipidosome is independent of inflammasome activation. Small interfering RNA knockdown and confocal microscopy studies showed that GTPases Rab5c, Rab40c along with JNK1 are essential for lipidosome formation and LTB4 production. BI-78D3, a JNK inhibitor, abrogated CS-induced neutrophilic inflammation in vivo in an air pouch model. These results highlight an inflammasome-independent and JNK activation-dependent lipidosome pathway as a regulator of LTB4 synthesis and CS-induced sterile inflammation.

• Authors: Bindu Hegde, Sobha R Bodduluri, Shuchismita R Satpathy, Ruqaih S Alghsham, Venkatakrishna R Jala, Silvia M Uriarte, Dong-Hoon Chung, Matthew B Lawrenz, Bodduluri Haribabu
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 200 Issue 10 Pg. 3556-3567 (05 15 2018) ISSN: 1550-6606 [Electronic] United States
• PMID: 29610142 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 by The American Association of Immunologists, Inc.

Chemical References

• Inflammasomes
• Interleukin-1beta
• NLR Family, Pyrin Domain-Containing 3 Protein
• Leukotriene B4
• Silicon Dioxide
• Mitogen-Activated Protein Kinase 8
• rab GTP-Binding Proteins
• rab5 GTP-Binding Proteins

Topics

• Animals
• Cell Line
• Humans
• Inflammasomes (metabolism)
• Inflammation (chemically induced, metabolism)
• Interleukin-1beta (metabolism)
• Leukotriene B4 (metabolism)
• Macrophages (drug effects, metabolism)
• Mast Cells (drug effects, metabolism)
• Mice
• Mice, Inbred C57BL
• Mitogen-Activated Protein Kinase 8 (metabolism)
• NLR Family, Pyrin Domain-Containing 3 Protein (metabolism)
• Neutrophils (drug effects, metabolism)
• Phagosomes (drug effects, metabolism)
• RAW 264.7 Cells
• Silicon Dioxide (pharmacology)
• Silicosis (metabolism)
• rab GTP-Binding Proteins (metabolism)
• rab5 GTP-Binding Proteins (metabolism)