Role of inflammasomes and lysosomal pathway in cell death and immunity induced by flagellin.

Author(s)

Silvia Lucena Lage

• Document type: Doctoral Thesis
• Press: São Paulo.
• Institution: Universidade de São Paulo (USP). Instituto de Ciências Biomédicas (ICB/SDI)
• Defense date: 2015-11-24

Examining board members

Karina Ramalho Bortoluci; Alexandre Salgado Basso; Alessandra Pontillo; Daniela Santoro Rosa; Ricardo Weinlich

• Advisor: Karina Ramalho Bortoluci

Abstract

Flagellin is a natural agonist of TLR5 and NAIP/NLRC4 inflammasome that is responsible for IL-1β and IL-18 secretion and for the induction of a necrotic cell death, both mediated by caspase-1. However, we observed that flagellin from B. subtilis inserted into lipid vesicles, induced an atypical cell death in peritoneal macrophages (PMs) in the absence of NLRC4, ASC and caspase-1/11. This inflammasome-independent cell death retained its antimicrobial outcome, being accompanied with IL-1α secretion. Importantly, cell death and caspase-1-dependent IL-1α and IL-1β secretion were regulated by lysosomal cathepsins, suggesting a cooperation between the inflammasome and lysosomal pathway in response to flagellin. We also observed that flagellin from S. typhimurium is able to induce lysosomal damage and IL-1α and IL-1β secretion by PMs in the absence of a carrier, through a caspase-catepsins-dependent manner, and that cytokines were important to the ability of flagellin in to induce adaptive immune response by antigen-specific T cells. (AU)

• FAPESP's process: 11/08502-0 - Cell death processes involvement in the flagellin adjuvant properties
• Grantee: Silvia Lucena Lage
• Support Opportunities: Scholarships in Brazil - Doctorate