NLRP3 inflammasome activation in the macrophage on the left is indicated by the ability to visualize the NLRP3 inflammasome complex (identified by the large yellow puncta). When calcium signaling is blocked pharmacologically in the cell on the right, inflammasomes are not activated, underscoring the critical role of calcium signaling in activation of the NLRP3 inflammatory pathway.
HSPH researchers uncover how a key inflammatory pathway is regulated
July 2, 2012 – Findings could help identify new therapeutic targets for inflammatory diseases
A team of scientists led by Harvard School of Public Health (HSPH) researchers has discovered how a protein complex known as the NLRP3 inflammasome, part of the immune system, is activated to trigger inflammation in the body. The findings should help scientists trying to unravel the mechanistic basis of inflammation associated with obesity, diabetes, cancer, autoimmune diseases, infection, and other physiological settings.
The study was published June 25, 2012 in an early online edition of Proceedings of the National Academy of Sciences (PNAS).
The investigators found that calcium signaling triggers mitochondrial damage to activate the NLRP3 inflammasome, which leads in turn to inflammation. Armed with this knowledge, researchers may be able to uncover new therapeutic targets for inflammatory diseases.
“Since its discovery several years ago, the NLRP3 inflammasome has been implicated in many inflammatory diseases, but how it is activated was not well understood. Our findings shed light on the regulation of this important inflammatory pathway,” said senior author Tiffany Horng, assistant professor of genetics and complex diseases at HSPH.
In addition to common inflammatory diseases, the new finding may lead to drug treatments for a cluster of rare autoinflammatory diseases called CAPS (Cryopyrin associated periodic syndrome), which is caused by mutations in NLRP3. Moreover, the findings suggest ways to boost NLRP3 inflammasome activity in other settings where inflammation may be beneficial, for example during infection by some pathogens, which subvert the NLRP3 inflammasome pathway to evade the immune response and thrive in the host.
Horng and her colleagues used a combination of genetic, pharmacological, and cell biological approaches, both in cell cultures and in mouse models, to identify the molecular mechanisms leading to NLRP3 inflammasome activation.
By revealing the molecular underpinnings of the NLRP3 inflammasome pathway, the study lays the foundation for further mechanistic studies. “Modulation of calcium-mediated mitochondrial damage could be a potential new candidate in treatment of inflammatory diseases,” said lead author Tomohiko Murakami, a postdoctoral fellow at HSPH.
Funding for the study came from the Harvard Digestive Diseases Center Pilot Fund and the HSPH Career Incubator Fund.
Photo courtesy of Tomohiko Murakami