In this blog, we will look at two papers that examine the relationship between mitochondrial function, autophagy, and NLRP3 inflammasome-mediated inflammation. This will include the special case of autophagy of mitochondria called mitophagy.
Autophagy allows your body to break down and reuse old cell parts so your cells can operate more efficiently. It’s a natural cleaning out process that begins when your cells are stressed or deprived of nutrients. Researchers are studying autophagy’s role in potentially preventing and fighting disease.
Mitochondria are membrane-bound cell organelles (the powerhouse of our cells) that generate most of the chemical energy needed to power the cell’s biochemical reactions. Chemical energy produced by the mitochondria is stored in a small molecule called adenosine triphosphate (ATP).
If your body is not undergoing autophagy, you are going to be more inflamed, more Th2 dominant as well as Th17 and your autoimmune process will progress more. Autophagy is essential. This blog is breaking down the science behind it and how to encourage autophagy/mitophagy. It is going to get technical but follow along and let me know in the forums if you have any questions!
The first paper we will look at (Harris, Mitochondrion, 2018) demonstrates that a failure of autophagy/mitophagy can lead to upregulation of inflammatory cytokines, including IL-1α, IL-1β, IL-18, type I IFN and lead to subsequent promotion and release of IL-23 and IL-17 which drives Th2, Th9 and Th17 dominance.
We know that formation of the autophagosome depends on IFNɣ and is inhibited by IL-4. Formation of the autophagosome is the first step in autophagy/mitophagy, so autophagy/mitophagy can go forward when there’s adequate Th1 response to make IFNɣ and also requires that there not be so much Th2 response that the IL-4 shuts down autophagosome formation. To recap, you need enough of a Th1 immune response to allow autophagy to go forward and not too much Th2 response or it is inhibited.
We already know that IFNɣ inhibits Th17 cells from making their effector cytokines. Loss of adequacy of the Th1 response yields an increase in Th17 effector cytokines, which increase inflammation and autoimmune tissue destruction. When the Th1 response is insufficient, so that autophagy/mitophagy are reduced, the other effect is a direct activation of IL-23 and IL-17. In other words, this is a second way that loss of Th1 response upregulates Th17, via inability to promote autophagy/mitophagy.
Also, measures taken to upregulate autophagy/mitophagy could be expected to help with inflammasome inhibition, downregulating inflammation and diminishing autoimmune-mediated tissue destruction. So for anyone with chronic inflammation, upregulating autophagy and promoting Th1 immune response (if needed) can help reduce tissue destruction and flares.
Autophagy/mitophagy are upregulated by IFNɣ and downregulated by IL-4. The papres shared below that we are using as reference for this post help us fill out the picture connecting autophagy/mitophagy, inflammation, autoimmunity, and T cell polarization.
it is important to remember from previous posts that there are implications for pathogen burdens, for brain function, and for energy production, among other biological endpoints.
Here are the key summary points to understand/remember:
- Autophagy/mitophagy and NLRP3 inflammasome activation are reciprocally inhibitory.
- Activation of mitophagy can function as a way to push back against excessive NLRP3-mediated inflammatory and/or autoimmune upregulation.
- NLRP3-mediated inflammatory activation upregulates inflammatory cytokines, including IL-17 and IL-23. We know that IL-17, as a Th17 effector cytokine, drives macrophage production of IL-6 (inflammatory cytokine). And we know that IL-6 and IL-23 are differentiation cytokines that drive naïve T cells to become Th17 cells. So, loss of Th1 leads to loss of mitophagy which caused increased NLRP3 activation and therefore increase in inflammatory cytokines, including Th17 differentiation cytokines. This elicits a Th17 response which drives inflammation and autoimmune tissue destruction. Again, a second way to arrive at Th17-mediated destruction from loss of Th1.
- Autophagy/mitophagy are promoted by IFNɣ, a Th1 cytokine, and inhibited by IL-4, a Th2 cytokine.
- And from the previous blog post, remember that vitamin D is necessary for M1 macrophage IFNɣ-mediated activation of autophagy.
So what do we do with this information?
You can consider implementing the following into your supplement and lifestyle regime (always check with your doctor or practitioner before following these tips):
- Urolithin A – a substance shown to promote mitophagy – Pure Encapsulations RENUAL supplement
- Address T cell polarization balance to promote autophagy / mitophagy by supporting adequate Th1 response and downregulating excessive Th2 dominance. This involves potentially supplementing with Berberine, Perilla, NAC and glutathione and sulforaphane.
- Support adequate vitamin D levels (if it is low)
- Promote SIRT2 to downregulate inflammasome activation. Remember also that low pH (high meat diet, etc.), low potassium, glycemic dysregulation, excessive fatty acids in circulation, etc., are inhibitors of SIRT2, so it’s important to address blood sugar imbalances, dietary factors related to pH, etc.
- Heat-based therapies like sauna (170* F, 20 minutes, at least 4x/week) or hot tub up to shoulders (104* F, 20 minutes, at least 4x/week). This induces mitochondrial activation/proliferation.
- Exercise to induce mitochondrial function/proliferation.
Research
Mitophagy and the release of inflammatory cytokines
Mitochondrion. 2018 Jul;41:2-8. Harris J, et al.
Interplay Between NLRP3 Inflammasome and Autophagy
Front Immunol. 2020 Oct 9;11:591803. Biasizzo M, Kopitar-Jerala N.
Immunologic manifestations of autophagy
J Clin Invest. 2015 Jan;125(1):75-84. Deretic V, Kimura T, Timmins G, et al.