Journal Article

Human caspase-4 mediates noncanonical inflammasome activation against gram-negative bacterial pathogens

Reyes, Valeria M., Taschuk, Frances O., Yu, Janet, Copenhaver, Alan M., Collman, Ronald G., Yadav, Anjana, Nguyen, Hieu T., Shin, Sunny, Casson, Cierra N.

2015

Overview

Significance The innate immune system provides a first line of defense against invading pathogens. The inflammasome is an innate immune complex that activates inflammatory caspases upon infection, causing cell death and IL-1 cytokine release, which initiate defense against gram-negative bacterial pathogens but also mediate septic shock. Many inflammasome studies have been performed using cells from mice, but mice and humans differ in their complement of inflammatory caspases. Instead of caspase-11, humans encode the putative orthologs caspase-4 and caspase-5. Here, we show that caspase-4 plays a conserved role in inflammasome activation in response to virulent gram-negative pathogens in primary human macrophages. Our findings provide important insight into how inflammasomes are regulated in human cells. Inflammasomes are critical for host defense against bacterial pathogens. In murine macrophages infected by gram-negative bacteria, the canonical inflammasome activates caspase-1 to mediate pyroptotic cell death and release of IL-1 family cytokines. Additionally, a noncanonical inflammasome controlled by caspase-11 induces cell death and IL-1 release. However, humans do not encode caspase-11. Instead, humans encode two putative orthologs: caspase-4 and caspase-5. Whether either ortholog functions similar to caspase-11 is poorly defined. Therefore, we sought to define the inflammatory caspases in primary human macrophages that regulate inflammasome responses to gram-negative bacteria. We find that human macrophages activate inflammasomes specifically in response to diverse gram-negative bacterial pathogens that introduce bacterial products into the host cytosol using specialized secretion systems. In primary human macrophages, IL-1β secretion requires the caspase-1 inflammasome, whereas IL-1α release and cell death are caspase-1–independent. Instead, caspase-4 mediates IL-1α release and cell death. Our findings implicate human caspase-4 as a critical regulator of noncanonical inflammasome activation that initiates defense against bacterial pathogens in primary human macrophages.

• Publisher: National Academy of Sciences,National Acad Sciences
• Subject: Animals / antigen-antibody complex / Bacteria / Biological Sciences / Caspase 1 - immunology / caspase-11 / caspase-4 / caspase-5 / Caspases, Initiator - immunology / Cell Death / Cells, Cultured / complement / Gram-Negative Bacteria - immunology / Gram-Negative Bacteria - pathogenicity / Humans / Inflammasomes - immunology / innate immunity / interleukin-1 / Interleukin-1alpha - metabolism / Interleukin-1beta - metabolism / Legionella pneumophila - immunology / Legionella pneumophila - pathogenicity / Lipopolysaccharides - toxicity / macrophages / Macrophages - enzymology / Macrophages - immunology / Macrophages - microbiology / Mice / pathogens / Salmonella typhimurium - immunology / Salmonella typhimurium - pathogenicity / septic shock / virulence / Yersinia pseudotuberculosis - immunology / Yersinia pseudotuberculosis - pathogenicity