Have you ever wondered what causes the body to create excess inflammation? At the root of the over-activation of inflammation for some people is NLRP3 inflammasome. This inflammasome is like an amplifier that cranks up the inflammatory response.
We will dig into the biology of the NLRP3 response as well as genetic variants that make people more susceptible to inflammatory chronic diseases.
What is NLRP3 and how is the inflammatory response system activated?
NRLP3 (NOD-like receptor, pyrin domain-containing 3 ) is a lynchpin for the activation of the inflammasome, which is the part of the immune system responsible for activating the body’s inflammatory response system.
Essentially, NLRP3 is a danger-sensing protein.
Inflammasomes are immune complexes that amplify the immune system response. The NLRP3 inflammasome is activated by:[ref]
- Pathogens (e.g. bacterial or viral infection)
- DNA replication errors in a cell (e.g. mutation that could cause cancer)
- Cellular damage, such as lysosomes breaking open, and mitochondrial dysfunction
Fighting off cancer and destroying bad microbes is really important! The inflammasome calls up the troops, amplifying the immune system response so that it is more powerful.
~ Balance is key ~
Excessive NLRP3 inflammasome activation causes chronic inflammation and increases susceptibility to a whole host of chronic diseases:
- rheumatoid arthritis
- cardiovascular disease
- Alzheimer’s disease
- type 2 diabetes
- eye diseases and dry eyes[ref]
What activates NLRP3?
NLRP3 hangs out in the cytosol of cells and is in an inactive form. It is mainly found in macrophages, a type of immune cell. NLRP3 is also found in a few other types of immune cells.[ref]
When activated, NLRP3 binds together to form a big complex with another protein called ASC.
So what activates NLRP3? The NLRP3 inflammasome recognizes and sounds the alarm for:[ref]
- viruses (e.g. adenovirus, influenza, Sendai virus, coronaviruses)
- some fungi (e.g. Saccharomyces cerevisiae, Candida albicans)
- bacteria (e.g. Listeria monocytogenes, Escherichia coli, Mycobacterium tuberculosis, and Staphylococcus aureus)
- parasites (e.g. Trichomonas vaginalis)[ref]
- asbestos and silica[ref]
- damage-associate factors in the body (uric acid crystal, beta-amyloid plaque, extracellular ATP) and ROS (reactive oxygen species)
Quick explanation: Activating NLRP3 causes a series of reactions to take place, resulting in increased inflammation.
More in-depth: When a pathogen or danger-associated factor triggers a receptor, such as a toll-like receptor or TNF-receptor, it causes an increase in the production of NLRP3. This ‘primes’ a cell to be ready for the pathogen or damage-associated factor. When the primed cell then comes in contact with the pathogen/damage signal, a series of reactions takes place with NLRP3 clustering together with ASC, resulting in the activation of caspase-1.
What happens when the NLRP3 inflammasome is activated?
When activated by a pathogen (e.g. gram-negative bacteria) or a cellular danger signal (e.g. ROS, ATP efflux, calcium flux), the NLRP3 inflammasome increases the secretion of pro-IL1β and IL-18. These are precursors to the inflammatory cytokines.
NLRP3 activation causes Caspase-1 to be activated. Caspase-1 acts as an enzyme to turn on the active version IL-1B, a strong inflammatory cytokine. Another inflammatory cytokine, IL-18 is also activated by caspase-1 via NLRP3.
This inflammatory cell death, pyroptosis, is a hard-core response to fight off pathogens inside a cell, such as certain bacteria and viruses. The abrupt cell death stops the microbes from replicating and allows the immune system to take care of them.
In cancer, NLRP3 is a double-edged sword. On the one hand, NLRP3 activation is important in destroying potential cancer cells through targeting DNA-damaged cells for pyroptosis. But chronic NLRP3 activation can lead to inflammatory or autoimmune conditions that are more likely to cause cancer.[ref][ref]
With such a powerful response, activation of NLRP3 when not needed can cause a lot of chronic problems in the body.
Over-activation of NLRP3:
Balance is the key with NLRP3 activation and most things in the body.
Chronic diseases associated with NLRP3 over-activation and/or NLRP3 genetic variants:
- Gout is caused by monosodium urate crystals in the joint. Monosodium urate is one trigger of NLRP3 activation of the inflammasome.[ref] (Learn more about genetic links to high uric acid.)
- Autoimmune diseases such as multiple sclerosis (MS). Over-activation of microglia and activation of the NLRP3 inflammasome are a big part of the problem in MS.[ref][ref]
- Alzheimer’s disease has links to amyloid-beta deposits in the brain. These amyloid-beta deposits activate the NLRP3 inflammasome, increasing IL-1B in the brain.[ref] NLRP3 activation may be part (all?) of the cause of the tau tangles. Animal research is still ongoing here.[ref] (Learn about APOE and Alzheimer’s risk.)
- Atherosclerosis, the build-up of plaque in the arteries, also involves NLRP3 activation and a chronic inflammatory response.[ref] Cardiolipin is a phospholipid that is part of the mitochondrial membrane. In atherosclerotic plaques, oxidized cardiolipin accumulates. Cardiolipin is one trigger of NLRP3 activation when it moves from the inner mitochondrial membrane to the outer membrane in mitochondrial dysfunction.[ref][ref][ref]
- Type 2 diabetes and insulin resistance have links to chronic low-grade inflammation due to NLRP3 activation. NLRP3 proteins, IL-1B and IL-18 upregulate in people with type 2 diabetes. One cause of this is mitochondrial ROS (reactive oxygen species).[ref][ref]
Rare auto-inflammatory diseases caused by NLRP3 mutations include:
- Cryopyrin-associated periodic fever syndrome (CAPS) is a rare autoinflammatory syndrome that can be caused by mutations in NLRP3. Symptoms include fever, itchy rash, conjunctivitis, headaches, hearing loss, and joint pain.[ref]
- Muckle-Wells syndrome is an auto-inflammatory syndrome caused by rare mutations in the NLRP3 gene. Researchers now consider this a type of CAPS.[ref] Symptoms include episodes of fever, chills, and painful joints. It is often exacerbated by cold. Additional symptoms of Muckle-Wells syndrome include recurrent conjunctivitis (pink eye), progressive hearing loss (later in life), and possibly amyloidosis.[ref]
- Familial cold auto-inflammatory syndrome is another milder subset of CAPS.[ref] Also caused by rare mutations in the NLRP3 gene, familial cold auto-inflammatory (or urticaria) syndrome is triggered by exposure to cold. Symptoms include fever, joint pain, and an itchy rash.[ref]
COVID-19 and NLRP3:
The SARS-CoV-2 coronavirus can cause COVID-19. Severe cases of COVID-19 have a strong inflammatory response going on in the body, causing damage that can lead to organ damage or death. Recent research shows the NLRP3 inflammasome activates in COVID-19 and may contribute to severity and mortality.[ref][ref] ( Discover links between genetics and the severity of COVID-19.)
Genetic variants in NLRP3:
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The following SNPs are linked in multiple peer-reviewed research studies to altered NLRP3 response. Please keep in mind that carrying the variant increases the relative risk of having the condition. In other words, carriers have an increased susceptibility but won’t always get the disease. Like most genetic variants, NLRP3 variants interact with other genes and environmental factors in causing disease.
NOTE: AncestryDNA and 23andMe data is not guaranteed to be clinically accurate for the rare mutations listed below. A clinical test is needed for confirmation of any rare pathogenic mutation.
NLRP3 gene (CIAS1): encodes the NLRP3 protein
Check your genetic data for rs35829419 Q705K (23andMe v4; AncestryDNA):
- A/A: Significantly increased susceptibility to leprosy, colorectal cancer, HIV-1 infection, rheumatoid arthritis, abdominal aortic aneurysms, inflammatory bowel disease, ulcerative colitis, and atopic dermatitis[ref] higher blood glucose levels after glycemic load[ref] higher disease activity in RA[ref];
- A/C: increased susceptibility to leprosy, colorectal cancer, HIV-1 infection, rheumatoid arthritis, abdominal aortic aneurysms, inflammatory bowel disease, ulcerative colitis, and atopic dermatitis; higher blood glucose after glycemic load
- C/C: typical
Members: Your genotype for rs35829419 is —. (If you don’t see your 23andMe v4 data for this one, check it on 23andMe. It doesn’t show up in some downloaded data sets.)
Check your genetic data for rs1539019 (23andMe v4, v5; AncestryDNA):
- C/C: most common genotype; lower risk of chronic hepatitis C[ref]
- A/C: typical risk
- A/A: increased relative risk of silica-dust caused pneumonia (e.g. coal workers)[ref]
Members: Your genotype for rs1539019 is —.
Check your genetic data for rs10754558 (23andMe v4; AncestryDNA):
- C/C: higher inflammation, increased relative risk of type 2 diabetes[ref] increased relative risk of ulcerative colitis[ref]
- C/G: somewhat increased inflammation
- G/G: typical
Members: Your genotype for rs10754558 is —.
Check your genetic data for rs3806265 (23andMe v4; AncestryDNA):
- C/C: may increase the relative risk of relapsing-remitting MS[ref] increased relative risk of juvenile idiopathic arthritis diagnosis[ref]
- C/T: may increase the relative risk of relapsing-remitting MS[ref] increased relative risk of juvenile idiopathic arthritis diagnosis[ref]
- T/T: typical
Members: Your genotype for rs3806265 is —.
Check your genetic data for rs10733113 (23andMe v4; AncestryDNA):
- A/A: somewhat higher NLRP3 levels[ref]
- A/G: somewhat higher NLRP3 levels
- G/G: typical
Members: Your genotype for rs10733113 is —.
Check your genetic data for rs12048215 (23andMe v4, v5; AncestryDNA):
- G/G: increased morbidity in sepsis (somewhat higher NLRP3)[ref]
- A/G: increased morbidity in sepsis
- A/A: typical
Members: Your genotype for rs12048215 is —.
Rare mutations in NLRP3:
Check your genetic data for rs121908148 (i5007539 23andMe v4):
- A/G: linked to familial cold urticaria[ref] (rare)
Members: Your genotype for i5007539 is —.
Check your genetic data for rs28937896 (23andMe v4, v5; AncestryDNA):
- C/T: linked to familial cold urticaria, autoinflammatory diseases[ref] (rare mutation)
- T/T: typical
Members: Your genotype for rs28937896 is —.
Check your genetic data for rs121908147 V200M, V198M (AncestryDNA):
- A/G: linked to familial cold urticaria and Muckle-Wells syndrome[ref] (rare mutation)
- G/G: typical
Members: Your genotype for rs121908147 is —.
Check your genetic data for rs121908150 R260W (AncestryDNA):
- C/T: linked to familial cold urticaria and Muckle-Wells syndrome[ref] (rare mutation)
- C/C: typical
Members: Your genotype for rs121908150 is —.
As always, check with your doctor or make sure that a supplement or diet change is right for you before implementing any of these ‘lifehacks’.
Get enough zinc: A recent animal study showed that zinc deficiency accelerated memory loss in a model of Alzheimer’s disease via increased NLRP3 inflammasome activation.[ref] Foods that are high in zinc include oysters, beef, crab, lobster, chicken, pork, and pumpkin seeds.[ref] Zinc supplements are also available if you don’t get enough via diet. Zinc supplements can cause stomach pain for some individuals, so you may want to choose a low-dose supplement, at least initially. (Read more about how genetic variants impact your need for zinc.)
EGCG, found in green tea, may help to suppress the activation of NLRP3. Research on EGCG in animal models of gout shows it to be effective in suppressing the activation of NLRP3 by urate crystal in gout.[ref]
Sufficient vitamin D levels are important in modulating the body’s inflammatory response. (Learn about the importance of Vitamin D genetic variants in the immune response.) The vitamin D receptor is a regulator of NLRP3 activation.[ref][ref] Animal studies show that vitamin D3 is important in inhibiting excessive NLRP3 activation.[ref][ref]
NLRP3 activation is important in insulin resistance and type 2 diabetes. The Mediterranean diet increased insulin sensitivity in non-diabetic NLRP3 variant carriers. Unfortunately, no benefit was seen for diabetic patients.[ref]
Glycyrrhizin (in licorice) inhibits NLRP3 in cell studies and animal studies.[ref] Be sure to check medication interactions, especially for high blood pressure, if you increase your intake of glycyrrhizin.
Oridonin is a component of the traditional Chinese medicinal herb Rabdosia rubescens. Studies show that it is a strong inhibitor of the NLRP3 inflammasome. Research (cells, animals) shows that it may be helpful in gout, arthritis, and acute lung injury.[ref]
Caffeic acid from honeybee propolis has some suppressive effects on NLRP3 levels.[ref]
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Immune System and Inflammation Topic Summary Report
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Mast cells: MCAS, genetics, and solutions
Mast Cell Activation Syndrome, or MCAS, is a recently recognized disease involving mast cells that are misbehaving in various ways. Symptoms of MCAS can include abdominal pain, nausea, itching, flushing, hives, headaches, heart palpitations, anxiety, brain fog, and anaphylaxis.
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