NLRP3: Genetics Variants that Increase Chronic Inflammation

Key takeaways:
~ The NLRP3 inflammasome senses pathogens and cell damage and then increases inflammatory response.
~ This inflammasome is like an amplifier that cranks up the inflammatory response.
~ Genetic variants in NLRP3 can cause the over-activation of inflammation for some people, leading to chronic diseases such as RA, heart disease, gout, and more.

What is NLRP3, and how is the inflammatory response system activated?

NLRP3 (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 and able to overwhelm the pathogens.

~ Balance is key with NLRP3~

Excessive NLRP3 inflammasome activation causes chronic inflammation and increases susceptibility to a whole host of chronic diseases:

• IBD
• rheumatoid arthritis
• cardiovascular disease
• Alzheimer’s disease
• type 2 diabetes
• gout
• 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)
• Specific fungi (e.g., Saccharomyces cerevisiae, Candida albicans)
• Bacterial RNA (e.g., Listeria monocytogenes, Escherichia coli, Mycobacterium tuberculosis, and Staphylococcus aureus)[ref]
• Certain 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)

Activating NLRP3 causes a series of reactions to take place, resulting in increased inflammation.

NLRP3 primes for inflammatory response: 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 take 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.

These two powerful pro-inflammatory cytokines then cause pyroptosis, an inflammatory form of cell death.[ref][ref]

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 by targeting DNA-damaged cells for pyroptosis. However, 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 key in 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.)
• 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]
• Autoimmune diseases such as multiple sclerosis (MS). The over-activation of microglia and the activation of the NLRP3 inflammasome are big parts 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.)
• 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 mutations that cause a gain-of-function in NLRP3 can cause genetic autoinflammatory conditions. While uncommon, understanding these conditions gives us a picture of what overactivation of NLRP3 can lead to.

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 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 that impact NLRP3 activation:

Variants that increase the function of the NLRP3 gene are linked to many different chronic diseases that are caused by excess inflammation.

Overactivation of NLRP3 can also cause someone to have a more severe reaction to a viral or bacterial illness. For example, the rs35829419 A allele increases NLRP3 activation in response to acute infection. People with the variant had a 13-fold increased risk of having  ‘Fatigue’, ‘Musculoskeletal pain’, ‘Mood disturbance’, and ‘Acute sickness’ while sick with Epstein-Barr virus (e.g. mono), Q fever, or a mosquito-born infection.[ref]

Variants that increase NLRP3 activation can also be a problem in transplant recipients. For example, a study showed that variants increasing NLRP3 are associated with acute rejection of kidney transplantation, while a loss-of-function NLRP3 mutation decreased the risk of rejection.[ref]

Tradeoffs: Keep in mind that a strong inflammatory response may be of benefit in fighting off certain infectious diseases. It is likely that the NLRP3 variants are found in the human population because they gave our ancestors an advantage in surviving a pathogen. It’s a balance, though, with too much of an inflammatory response to a pathogen being detrimental, especially in the elderly.

Lifehacks:

If you have genetic variants that increase NLRP3 activation, consider whether tamping down the overactivation would be helpful for you. In general, you don’t want an overactive immune response, but if you are on immunosuppressant drugs, it may not be a good idea to further suppress NLRP3 activation. 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’. 

Dietary considerations for decreasing NLRP3 activation:

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 your diet.

Related article: Genetic variants impact your need for zinc

Sufficient vitamin D levels:
Vitamin D is important in modulating the body’s inflammatory 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]

Related article: Vitamin D genetic variants in the immune response

Healthy diet:
NLRP3 activation plays a role in insulin resistance. The Mediterranean diet increased insulin sensitivity in non-diabetic NLRP3 variant carriers. Unfortunately, no benefit was seen for diabetic patients.[ref]

Natural supplements that decrease inflammation via NLRP3:

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