A new understanding of one of the body's immune defense mechanisms could lead to the development of novel therapeutic targets for conditions such as cancer and autoimmune diseases, a University of Queensland study has revealed.

Neutrophil extrusion of neutrophil extracellular traps (NETs) and concomitant cell death (NETosis) provides host defense against extracellular pathogens, whereas macrophage death by pyroptosis enables defense against intracellular pathogens.

They reported the unexpected discovery that gasdermin D (GSDMD) connects these cell death modalities. They showed that neutrophil exposure to cytosolic lipopolysaccharide or cytosolic Gram-negative bacteria (Salmonella ΔsifA and Citrobacter rodentium) activates noncanonical (caspase-4/11) inflammasome signaling and triggers GSDMD-dependent neutrophil death. 

GSDMD-dependent death induces neutrophils to extrude antimicrobial NETs. Caspase-11 and GSDMD are required for neutrophil plasma membrane rupture during the final stage of NET extrusion.

The immune system

Unexpectedly, caspase-11 and GSDMD are also required for early features of NETosis, including nuclear delobulation and DNA expansion; this is mediated by the coordinated actions of caspase-11 and GSDMD in mediating nuclear membrane permeabilization and histone degradation.

UQ's Institute for Molecular Bioscience researcher Associate Professor Kate Schroder, along with Dr. Kaiwen Chen, Dr. Mercedes Monteleone, and Dr. Dave Boucher, uncovered a new line of defense deployed by the immune system against bacteria.

"Bacteria are often quickly killed by white blood cells called neutrophils, which are the body's initial line of defense against infection," Dr. Schroder said.

"We discovered an unexpected secondary line of defense that is deployed against bacteria that have evaded the initial immune response and invaded the neutrophil itself. This new immune defense pathway is mediated by an 'executioner' protein called Gasdermin D," Dr. Schroder said.

"This protein drives an unusual form of 'cellular suicide,' where the cell expels structures called neutrophil extracellular traps (NETs) to catch the infection and prevent it from spreading," Dr. Schroder said.

NETs are networks of DNA fibers embedded with antimicrobial proteins that immobilize and kill bacteria, providing a secondary line of resistance.

While researchers already knew that neutrophil cell death could be associated with NETs, this discovery revealed an entirely new pathway using Gasdermin D and the inflammasome – a molecular machine that senses and response to infection.

Dr. Schroder said while NETs had a protective role in fighting pathogens, they could also drive pathology in some autoimmune and inflammatory diseases, as well as cancers.

"It is important we understand the basic cellular mechanisms of inflammation before we develop treatments for various immune-related diseases," Dr. Schroder said.

"Understanding how the Gasdermin D drives neutrophil death and the expulsion of NETs could lead to new therapeutic targets for immune-related diseases, which could, in turn, lead to more effective treatments and improve quality of life for affected individuals."