Our innate immune cells triage danger signals

Jelena Bezbradica, Rebecca Coll and Kate Schroder from the Inflammasome Lab have uncovered a hierarchy of inflammasome responses to different types of cellular dangers, suggesting that our immune cells triage danger signals. The discovery was recently accepted for publication in the journal Cellular & Molecular Immunology.

Our immune cells, like macrophages, sense danger through a broad repertoire of immune receptors on the cell's surface. These signalling systems are interconnected through multiple layers of signal cross-talk to inflammasomes inside the cell - protein complexes at the heart of inflammation (eg. illustrated in the image above). Broadly, there are two types of inflammation: inflammation to restore homeostasis following a sterile injury and inflammation in response to a microbial infection, to both eradicate the microbe and induce protective immunity. We performed the first direct side-by-side comparison of NLRP3 inflammasome responses to these two triggers of inflammation. In both mouse and human macrophages, we discovered that sterile signals (TNF and ATP) exhibited delayed and weaker abilities to both prime and activate an NLRP3 response, when compared to microbial priming and activating signals (LPS and nigericin). This discovery, that sterile versus microbial signals trigger distinct responses, may be an important factor in the design of new drugs to treat inflammatory diseases.

 

Bezbradica JS1, Coll RC1 and Schroder K (2016).
Sterile signals generate weaker and delayed macrophage NLRP3 inflammasome responses relative to microbial signals. Cellular & Molecular Immunology In press. Pubmed
1Equal contribution
 

 

Abstract

Inflammation is the host response to microbial infection or sterile injury that aims to eliminate the insult, repair the tissue and restore homeostasis. Macrophages and the NLRP3 inflammasome are key sentinels for both types of insult. Although it is well established that the NLRP3 inflammasome is activated by microbial products and molecules released during sterile injury, it is unclear whether the responses elicited by these different types of signals are distinct. In this study, we used lipopolysaccharide and tumor necrosis factor as prototypical microbial and sterile signal 1 stimuli, respectively, to prime the NLRP3 inflammasome. We then used the bacterial toxin nigericin and a common product released from necrotic cells, ATP, as prototypical microbial and sterile signal 2 stimuli, respectively, to trigger the assembly of the NLRP3 inflammasome complex in mouse and human macrophages. We found that NLRP3 inflammasome responses were weakest when both signal 1 and signal 2 were sterile, but responses were faster and stronger when at least one of the two signals was microbial. Ultimately, the most rapid and potent responses were elicited when both signals were microbial. Together, these data suggest that microbial versus sterile signals are distinct, both kinetically and in magnitude, in their ability to generate inflammasome-dependent responses. This hierarchy of NLRP3 responses to sterile versus microbial stimuli likely reflects the urgent need for the immune system to respond rapidly to the presence of infection to halt pathogen dissemination.

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ABOUT Inflammasome Lab

Inflammasome Lab is a group of researchers led by Dr Kate Schroder at the Institute for Molecular Bioscience, The University of Queensland.
We seek to unravel the secrets of inflammasomes – protein complexes at the heart of inflammation and disease – to allow for new therapies to fight human diseases.