Inflammation has a bad reputation, and mostly an undeserved one. The swelling around a cut and the fever that comes with an infection are your immune system doing its job. The trouble starts when the alarm will not switch off. Deep inside many immune cells sits a small machine that decides when the alarm goes off, and it has become one of the most studied structures in modern biochemistry.
Inflammation is an alarm, not a villain
When bacteria get in, or cells are damaged, the body needs to act fast: send in more immune cells, raise the temperature, repair tissue. Inflammation is that response. Short bursts protect you. Long, low-level inflammation that never quite settles is a different story. It is now linked, in research, to conditions as different as type 2 diabetes, heart disease and neurodegenerative disease.
So a natural question for scientists is this: what flips the switch? Part of the answer is a protein complex called the inflammasome.
What an inflammasome actually is
An inflammasome is a cluster of proteins that assembles inside a cell, in the fluid of its interior, when the cell senses trouble. The term was coined in 2002 by Jürg Tschopp's group in Switzerland, who described a platform that switches on inflammatory enzymes.1 Three kinds of part do the work:
- A sensor, such as the protein NLRP3, that detects signs of danger.
- An adaptor, called ASC, that links the sensor to the next part.
- An enzyme, pro-caspase-1, which is made in an inactive form and activated when the complex forms.
NLRP3 is the best studied of several inflammasomes, mostly because it responds to so many different triggers and has been connected to so many diseases.2
Two signals, not one
NLRP3 is deliberately hard to switch on. A cell usually needs two separate signals, a bit like a safe that needs two keys.
Signal 1 is priming. Receptors on the cell surface, such as TLR4, which recognizes components of bacteria, pass a message inward. That message activates a transcription factor called NF-κB, which turns on the genes for NLRP3 itself and for the inactive form of a powerful inflammatory messenger, pro-IL-1β. At this stage nothing is sounding. The cell has simply stocked the parts.
Signal 2 is activation. A second, separate trigger tells NLRP3 that something is wrong inside the cell. The list of triggers is long and strangely varied: potassium leaking out of the cell, damaged mitochondria releasing reactive oxygen species, ruptured lysosomes, and crystals such as uric acid, which is the cause of gout.6 It is unlikely that NLRP3 binds each of these directly. The leading view is that it senses a shared state of cellular stress, although exactly how is still debated.
From wheel to alarm
Once triggered, NLRP3 proteins gather into a wheel-shaped structure and recruit ASC, which clumps into a single bright speck that researchers can see under a microscope. Pro-caspase-1 is pulled in and activates itself. Active caspase-1 then does two jobs.
- It cuts pro-IL-1β and pro-IL-18 into their active forms. These are the signals that tell other immune cells to join in.
- It cuts a protein called gasdermin D. The fragments punch pores in the cell membrane, which lets the messengers out and can cause the cell to burst in a controlled form of death called pyroptosis.
That is the whole sequence: stock the parts, sense the danger, assemble, cut, release. It is fast, it is loud, and the cell pays for it, which is why the switch is so tightly guarded.
Why researchers care so much
When the switch sticks, people get ill. Mutations that make NLRP3 overactive cause a family of rare inherited fevers, first linked to the gene in 2001, which respond to drugs that block IL-1.3 The wider interest is in common diseases. Cholesterol crystals in artery walls can activate NLRP3, and in a large clinical trial an antibody against IL-1β lowered the rate of further heart attacks, strokes and cardiovascular deaths in people who had already had a heart attack and still showed signs of inflammation, which was strong evidence that inflammation itself is a treatable part of the problem.4 In mouse models of Alzheimer's disease, NLRP3 activity in the brain's immune cells contributes to pathology.5
That is why so many labs are looking for ways to dial the pathway down: synthetic molecules, and also compounds from plants and foods, usually tested first in cells and then in animals.
What this does and does not tell you
A few honest limits. Most of what is known about NLRP3 comes from cell cultures and mice, and results in mice often fail to carry over to people. A compound that quiets the pathway in a dish is a starting point, not evidence that a supplement will help you. And you do not want to switch the inflammasome off completely: people need it to fight infection.
The practical takeaway is modest and useful. Chronic inflammation is shaped by sleep, movement, body weight, diet and stress, and each of those has stronger evidence behind it than any single product. The inflammasome is part of the explanation of why.
References
- Martinon F, Burns K, Tschopp J. The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-β. Mol Cell. 2002;10(2):417–426. Find it ↗
- Swanson KV, Deng M, Ting JP-Y. The NLRP3 inflammasome: molecular activation and regulation to therapeutics. Nat Rev Immunol. 2019;19:477–489. Find it ↗
- Hoffman HM, Mueller JL, Broide DH, Wanderer AA, Kolodner RD. Mutation of a new gene encoding a putative pyrin-like protein causes familial cold autoinflammatory syndrome and Muckle–Wells syndrome. Nat Genet. 2001;29:301–305. Find it ↗
- Ridker PM, Everett BM, Thuren T, et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med. 2017;377:1119–1131. Find it ↗
- Heneka MT, Kummer MP, Stutz A, et al. NLRP3 is activated in Alzheimer’s disease and contributes to pathology in APP/PS1 mice. Nature. 2013;493:674–678. Find it ↗
- Martinon F, Pétrilli V, Mayor A, Tardivel A, Tschopp J. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature. 2006;440:237–241. Find it ↗
Educational content, not medical advice. If you have a health concern, speak to a qualified professional.