Inherently Reduced Expression of ASC Restricts Caspase-1 Processing in Hepatocytes and Promotes Plasmodium Infection

Camila Marques-Da-Silva, Clyde Schmidt-Silva, Rodrigo P. Baptista, Samarchith P. Kurup

Research output: Contribution to journalArticlepeer-review

Abstract

Inflammasome-mediated caspase-1 activation facilitates innate immune control of Plasmodium in the liver, thereby limiting the incidence and severity of clinical malaria. However, caspase-1 processing occurs incompletely in both mouse and human hepatocytes and precludes the generation of mature IL-1β or IL-18, unlike in other cells. Why this is so or how it impacts Plasmodium control in the liver has remained unknown. We show that an inherently reduced expression of the inflammasome adaptor molecule apoptosis-associated specklike protein containing CARD (ASC) is responsible for the incomplete proteolytic processing of caspase-1 in murine hepatocytes. Transgenically enhancing ASC expression in hepatocytes enabled complete caspase-1 processing, enhanced pyroptotic cell death, maturation of the proinflammatory cytokines IL-1β and IL-18 that was otherwise absent, and better overall control of Plasmodium infection in the liver of mice. This, however, impeded the protection offered by live attenuated antimalarial vaccination. Tempering ASC expression in mouse macrophages, on the other hand, resulted in incomplete processing of caspase-1. Our work shows how caspase-1 activation and function in host cells are fundamentally defined by ASC expression and offers a potential new pathway to create better disease and vaccination outcomes by modifying the latter.

Original languageEnglish (US)
Pages (from-to)596-606
Number of pages11
JournalJournal of immunology (Baltimore, Md. : 1950)
Volume212
Issue number4
Early online dateDec 27 2023
DOIs
StatePublished - Feb 15 2024

Keywords

  • Adaptor Proteins, Signal Transducing/metabolism
  • Animals
  • Apoptosis Regulatory Proteins/metabolism
  • CARD Signaling Adaptor Proteins/metabolism
  • Caspase 1/metabolism
  • Hepatocytes/metabolism
  • Humans
  • Inflammasomes/metabolism
  • Interleukin-18/metabolism
  • Interleukin-1beta/metabolism
  • Malaria
  • Mice
  • Mice, Knockout
  • NLR Family, Pyrin Domain-Containing 3 Protein/metabolism

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Fingerprint

Dive into the research topics of 'Inherently Reduced Expression of ASC Restricts Caspase-1 Processing in Hepatocytes and Promotes Plasmodium Infection'. Together they form a unique fingerprint.

Cite this