Nutritional Modulation of NLRP3 Inflammasome

Inflammation is a necessary response, and it can initiate host defense response and repair damaged tissue. However, an uncontrolled inflammatory signal can cause prolonged inflammatory cytokines production, resulting in serious disorders and tissue damage. Nevertheless, the inflammation process can be described and a cascade sequence in which IL-1b plays a fundamental part. As part of the cascade sequence, the proinflammatory cytokine IL-1b requires to be activated by a multiprotein complex called the inflammasome. To modulate this inflammatory cascade, nutritional modulation can contribute by interacting with the NLRP3 inflammasome pathway.

What is an inflammasome?

As mentioned before, inflammasomes are multiprotein complexes. They are part of the innate immune system. Consequently, inflammasomes have the primary role of initiating the inflammation cascade when a bacterial or viral infection occurs.  Furthermore, one of the most studies inflammasome is NLRP3, which is comprised of NLRP3 sensor, ASC (Apoptosis-associated speck-like protein containing a CARD) adaptor, and caspase-1 protease.

NLRP3 (NOD-like receptor pyrin domain containing 3)

NOD-like receptors are considered a pattern recognition receptor (PPR) that sense a wide range of PAMPs (pathogen-associated molecular patterns). Besides this, NLRP3 can recognize damage-associated molecular patterns (DAMPs). Furthermore, when the PPR senses a disturbing presence, it changes and turns into a PPR oligomer. Once the PPR oligomer is formed, the ASC can be recruited from the cytoplasm. Later, this PPR-ASC dimer can recruit dormant caspases and activate them. Lastly, this caspase activation results in the cleavage of inflammatory cytokines such as pro-interleukin-1B (pro- IL-1B) and pro-IL-18.

IL-1b

The activation of IL-1b must be tightly regulated; this is why it requires two signals to become functional.

Priming: The first activating signal. It is fueled when PAMPs get sensed by TLR, followed by the induction of the inflammasome components. Furthermore, this signal upregulates the inactive cytokine precursor pro-IL-1b.

Second signal: This signal is mediated by DAMPs and PAMPs, ultimately leading to the assembly between the ASC and caspase-1. Consequently, the caspase-1 cleavage initiates the secretion of proinflammatory cytokine IL-1b.

NLRP3 activation mechanisms:

• Intracellular release of oxidized mitochondrial DNA (mtDNA).
• Decreased intracellular cAMP level.
• Formation of bacterial toxins.
• Presence of reactive oxygen species (ROS).
• Potassium (K+) efflux.

The main function of inflammasome activation is to protect the host against invading organisms. However, several endogenous (self-derived) factors can induce the NLRP3 leading to allergic responses or other diseases.

Natural compounds Interfering with NLRP3 activation.

The conventional approach to treat every ill with a pill is vastly applied to inhibit NLRP3’s activation. Nevertheless, natural alternatives are part of the solution. Also, patients are interested in treating their inflammatory and autoimmune disorders with natural compounds. Besides this, these botanical compounds have evidence-based studies that assure their influence over a multitude of pathways.

Aloe Vera:

The curative effects of Aloe Vera gel are reported to induce wound-healing, hematopoiesis, and skin hydration effects. Besides this, aloe vera has been used to treat diabetes, microbial infections, and cancer, all due to its anti-inflammatory and antioxidant effects.

As an anti-inflammatory, Aloe vera can inhibit TNF-a, IL-6, and IL-1b levels. Besides this, LPS- induced IL-1b production is reduced with Aloe vera treatment. Another important Aloe vera effects are the inhibition of pro-IL-1b, NLRP3, and caspase-1, resulting in the downregulation of NF-kB.

Curcumin:

This polyphenol is derived from turmeric, a yellow spice widely used in many cultures as pigment or flavor. However, the potent anti-inflammatory, antioxidant and antimicrobial effects of curcumin have positioned it as a potential therapeutic agent. Indeed, curcumin has widely studied clinical applications on cancer, autoimmune, inflammatory diseases, neural pathologies, and metabolic conditions such as cardiovascular and pulmonary illnesses.

In mouse models, glucose deprivation and hypoxia lead to an overproduction of glutamate and IL-1b on the hippocampus. Furthermore, when mice got pretreated with curcumin, the production of IL-1b was attenuated by AMPK. Also, curcumin was able to modulate glutamate-induced phosphorylation, resulting in reduced inflammatory signaling.

Adding to these benefits, curcumin can inhibit the glutamate-induced activation of NRLP3, as well as the cleavage of ASC to caspase-1. Consequently, this reaction leads to the downstream blockage of IL-6 and IL-1b.

The activation of the inflammatory response is crucial for host defense. However, inflammation must exist in a coordinated environment when inhibitory factors can intervene and control this response. Therefore, we must understand that inflammation will always be part of our lives and control it. The inclusion of anti-inflammatory compounds in our diet is a therapeutic option to assess. Indeed, the evidence supports that these agents can act at a molecular level to reduce inflammation. – Ana Paola Rodríguez Arciniega, MS

References:

Tőzsér, József, and Szilvia Benkő. “Natural Compounds as Regulators of NLRP3 Inflammasome-Mediated IL-1β Production.” Mediators of inflammation vol. 2016 (2016): 5460302. doi:10.1155/2016/5460302

Song, Nan, and Tao Li. “Regulation of NLRP3 Inflammasome by Phosphorylation.” Frontiers in immunology vol. 9 2305. 8 Oct. 2018, doi:10.3389/fimmu.2018.02305

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Dr. Alex Jimenez DC, MSACP, CCST, IFMCP*, CIFM*, CTG*

email: coach@elpasofunctionalmedicine.com
phone: 915-850-0900
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