Inflammasomes and MS: How NLRP3 Drives Neuroinflammation and What You Can Do About It

In this blog I will review a recent paper on the molecular mechanisms that drive disability progression in multiple sclerosis (MS), Alzheimer's, Parkinson’s, and many chronic disease states. I will also give specific recommendations to address those issues. 

Increased NLRP3 drives worsening of inflammation in the central nervous system 

The recent paper, NLRP3 Inflammasome in Neuroinflammation and Central Nervous System Diseases ⁽¹⁾, reviews the role of the NLRP3 molecule in multiple sclerosis (MS), Parkinson’s, Alzheimer’s, stroke, and other neurological diseases.

NLRP3 acts like a fire alarm for your immune system, triggering inflammation in response to damage or infection. Elevated NLRP3 can drive increased production of two key inflammatory molecules, cytokines IL-1β and IL-18, which further increase inflammation in the brain, spinal cord, and cranial nerves. This can accelerate damage and worsen symptoms for people with brain-related health issues.

In the central nervous system, increased NLRP3 also activates microglia—the brain’s resident immune cells. While microglia normally protect the brain, overactivation can turn them into a source of harm. In conditions like MS, overactive microglia contribute to the formation of new lesions and relapses, as well as brain and spinal cord atrophy (shrinkage). Over time, this leads to faster disability progression and worsening mood and cognitive problems.

DAMPs and PAMPs and the brain 

When molecules that should be inside the cell leak outside the cell, the neighboring cells interpret them as signals of cell damage that needs to be “cleaned up.” These signals are called damage-associated molecular patterns, or DAMPs.(2) Similarly, when proteins from infectious microbes or other pathogens are detected, the signals are called pathogen-associated molecular patterns, or PAMPs.⁽²⁾ Both DAMPs and PAMPs trigger an intense call for the immune system to take action—either to destroy any pathogens present or to digest the damaged cells so they can be replaced with healthier ones.

Once the pathogens and/or damaged cells are cleared, and no more DAMPs or PAMPs are detected, the immune system is supposed to go through a resolution phase, and then settle back into surveillance mode. Activation of the Nrf2 pathway facilitates the resolution of inflammation—and millions of dollars are currently being spent to develop drugs that stimulate this pathway.

However, there are several things we can do to reduce the amount of DAMPs and PAMPs in our systems lower NLRP3 activity, and support the resolution of inflammation.

Leaky gut and NLRP3

Having a leaky gut has been shown to increase the leakage of microbial proteins into the bloodstream, which in turn elevates NLRP3 levels.(3) Factors that can increase the risk of leaky gut include aspirin, alcohol use, smoking, ibuprofen (and other NSAIDS), and diets that are high in added sugar and white flour. Antibiotics taken in the first three years of life—or prolonged antibiotics in adulthood—also increase the risk of leaky gut and elevated NLRP3.

If you have ongoing pain, I recommend avoiding NSAIDs and instead trying an herbal product like Fast Relief. This formula suppresses the same COX pathways that ibuprofen and other NSAIDS target for pain relief, while supporting a healthy gut.^{(4, 5)} Additionally, I recommend reducing or eliminating added sugars and white flour-based foods, and adding more fermented foods like sauerkraut and kimchi into your diet.

Supplements that support resolution of elevated NLRP3 

Remember, activation of the Nrf2 pathway will facilitate the resolution of inflammation. Fortunately, there are many natural compounds available that can help reduce the damage caused by elevated NLRP3 levels. Omega-3 fatty acids, for example, activate the Nrf2 pathway and support the resolution of inflammation.^{(6, 7)} Additionally, specific polyphenols and antioxidants can stabilize cell membranes and activate the Nrf2 pathway to calm NLRP3. These include N-acetylcysteine (NAC), lipoic acid, acetyl-L-carnitine, coenzyme Q10, broccoli seed extract, and phosphatidylserine.^{(6, 7)}

Summary 

Elevated NLRP3 levels drive inflammation and accelerate disability across many brain-related diseases. The good news is that dietary changes and targeted supplements can help reduce NLRP3. Start by addressing leaky gut by reducing or eliminating smoking, alcohol, added sugars, and white-flour-based products. Incorporate more fermented foods like sauerkraut and kimchi into your diet, and replace ibuprofen and other NSAIDs with Fast Relief, an herbal alternative that supports gut health.

Consider adding MonoAbsorp for well-absorbed omega-3 fatty acids, and Brain Protect, which combines polyphenols and antioxidants into one supplement.

My patients have found these dietary changes and targeted supplements helpful for reducing fatigue, improving energy, and enhancing mental clarity. Reducing excess NLRP3 is essential if you want to thrive into your 70s, 80s, 90s, and beyond. That’s my goal—and I hope it’s yours as well.

Find any of the nutrients mentioned in my curated line of Wahls Protocol® Supplements. Subscribe and save 5% off your first order and 10% off every order after that. 

Shop Now! 

References:

1. Xu W, Huang Y, Zhou R. NLRP3 inflammasome in neuroinflammation and central nervous system diseases. Cell Mol Immunol. 2025.
2. Choi SB, Kwon S, Kim JH, Ahn NH, Lee JH, Yang SH. The Molecular Mechanisms of Neuroinflammation in Alzheimer's Disease, the Consequence of Neural Cell Death. Int J Mol Sci. 2023;24(14).
3. Solanki R, Karande A, Ranganathan P. Emerging role of gut microbiota dysbiosis in neuroinflammation and neurodegeneration. Front Neurol. 2023;14:1149618.
4. Haroyan A, Mukuchyan V, Mkrtchyan N, Minasyan N, Gasparyan S, Sargsyan A, et al. Efficacy and safety of curcumin and its combination with boswellic acid in osteoarthritis: a comparative, randomized, double-blind, placebo-controlled study. BMC Complement Altern Med. 2018;18(1):7.
5. Zeng L, Yang T, Yang K, Yu G, Li J, Xiang W, et al. Curcumin and Curcuma longa Extract in the Treatment of 10 Types of Autoimmune Diseases: A Systematic Review and Meta-Analysis of 31 Randomized Controlled Trials. Front Immunol. 2022;13:896476.
6. McCarty MF, Iloki Assanga SB, Lewis Lujan L, O'Keefe JH, DiNicolantonio JJ. Nutraceutical Strategies for Suppressing NLRP3 Inflammasome Activation: Pertinence to the Management of COVID-19 and Beyond. Nutrients. 2020;13(1).
7. Yang K, Zeng L, He Q, Wang S, Xu H, Ge J. Advancements in research on the immune-inflammatory mechanisms mediated by NLRP3 inflammasome in ischemic stroke and the regulatory role of natural plant products. Front Pharmacol. 2024;15:1250918.