My last blog post reviewed evidence of the involvement of trained immunity in several chronic inflammatory diseases. You may wonder what are the persistent stimuli that can trigger the innate immunity memory and cause the chronic inflammation that can result in inflammatory-related diseases. The answer is not the live attenuated vaccines, nor any invading pathogens, but the Western style of living. As Prof Netea and others wrote in a review paper, "there is increasing evidence that *sterile inflammation (a pathogen-free inflammation) in response to lifestyle changes in Western societies forms the basis on which chronic inflammatory diseases develop."1 Let us see the research studies that may give us an idea of how to prevent such chronic inflammatory diseases.
Western diet can induce trained immunity
According to the definition by scientists in the immunity field, the Western style of living includes consumption of a Western-type diet and sedentary behaviour. The Western-type diet, particularly the American diet, contains high calories and is rich in sugars, trans and saturated fats, salt and food additives, but low in complex carbohydrates, fibre, vitamins and minerals.2
In a study aimed at finding out if the Western-type diet can induce trained immunity, mice which were genetically modified so that they are prone to atherosclerosis, had high expression of genes related to inflammation and #epigenetic reprogramming in their circulating monocytes and their bone marrow myeloid progenitor cells, after being constantly fed with Western-type diet for 4 weeks. This shows that the Western-type diet induces systemic inflammation and long-lasting innate immune cell reprogramming, which amplifies responses to a secondary immune challenge.3
Even after the mice had been switched to a standard normal diet for another 4 weeks, and the serum cholesterol levels and systemic inflammatory markers returned back to normal, the functional reprogramming in myeloid cells still remained.3 The induction in innate immunity response remaining high indicates that the long-lasting reprogramming of the innate cells triggered by the previous Western-type diet could potentially contribute to chronic inflammatory diseases.
Key substances in a Western-type diet that induce trained immunity
Thus far, research studies have identified several @endogenous triggers of innate immunity. These include $lipoprotein(a) and %oxidized low-density lipoprotein.4,5 These studies found that oxidized low-density lipoprotein induces long-term cytokine production which promotes inflammation, and foam cell formation which is associated with atherosclerosis. The long-term cytokine production and foam cell formation are induced via epigenetic reprogramming of monocytes.
When &oxidized cholesterol in the diet is absorbed, it contributes to the pool of oxidized lipoprotein in human serum.6 The high fat Western-type diet thus provides a rich source of endogenous stimulation in form of oxidized low-density lipoprotein that can cause chronic inflammation by triggering a long-lasting innate immunity response via cellular reprogramming.
How does the Western-type diet cause the innate immunity to "memorize"?
The same research study which used mice models to demonstrate the triggering of long-lasting innate immunity by a chronic Western-type diet found that such a diet activates NLRP3 inflammasome, a key innate immune sensor for many environmental danger signals such as uric acid and cholesterol crystals, to induce system inflammation and reprogramming of innate immunity. Therefore, the Western-type diet appears to be mistakenly recognized by the immune system as a threat to the organism.3
What we can learn from these findings?
It is well established that diet high in fat and cholesterol is a risk factor for the development of atherosclerosis, and also for the development of other chronic inflammatory diseases, such as type 2 diabetes, obesity, and chronic liver disease. However, the above studies provide clear evidence that such a diet is mistakenly recognized by innate immunity as a danger signal. The persistent uptake of such a diet could contribute to chronic inflammatory reaction by triggering a long-lasting innate immunity.
Moreover, the fact that studies have shown the reprogramming of innate immune cells occurs via a change in the DNA chromatin level, has caused the emerging concept that ancestral environments and abnormal changes in body functions which are the causes, consequences, or concomitants of disease processes, can be transferred down through generations.
Are the findings from these studies powerful enough to make you determined to make changes to your diet?
*Sterile inflammation: A form of pathogen-free inflammation. This can be caused by mechanical trauma, stress, or environmental conditions. The sterile inflammation referred to in this post is caused by a Western-type diet. These damage-related stimuli induce the secretion of molecular agents, collectively termed danger-associated molecular patterns.
#Epigenetic reprogramming: A process that involves changing of methylation status of histones on the DNA's chromatin level. This results in a change of chromatin structure and hence of gene expression. Epigenetic reprogramming in innate immune cells usually results in the changing of expression of different inflammatory related genes. The change is reversible but usually can last for a few years. Therefore the epigenetic reprogramming in innate immune cells enables the cells to remember the stimulation and react more quickly next time. However, this can also cause chronic inflammation if the innate immune cells are persistently stimulated.
@Endogenous triggers: Stimuli from substances inside the body. In this post, these include lipoprotein(a) and oxidized low-density lipoprotein.
$Lipoprotein(a): This is a plasma lipoprotein composed of apolipoprotein(a) and apolipoprotein B-100 of a low-density lipoproteins-like particle. Lipoproteins are macromolecular complexes of lipid (cholesterol) and proteins that originate mainly from the liver and intestine, and are involved in the transport and redistribution of lipids (cholesterol) in the body.7 In other words, cholesterol travels through the blood on lipoproteins.
%Oxidized low-density lipoprotein: This is a product of chemical reactions between normal low-density lipoproteins and free radicals. It is potentially harmful, because a high level of low-density lipoprotein can lead to a build-up of cholesterol in arteries, which can cause blockages.
&Oxidized cholesterols: They are mainly generated by frying, heating, and processing of a high cholesterol, fat-rich diet.
References
1. M.G. Netea, J. Dominguez-Andres, L.B. Barreiro, et al. Defining trained immunity and its role in health and disease. Nat. Rev. Immunol., 2020, Jun;20(6): 375-388.
2. A. Christ, & E. Latz. The Western lifestyle has lasting effects on metaflammation. Nat. Rev. Immunol., 2019, 19, 267-268.
3. A. Christ, P. Gunther, M.A.R. Lauterbach, et al. Western diet triggers NLRP3-dependent innate immune reprogramming. Cell, 2018, 172, 162-175.
4. S. Bekkering, J. Quintin, L.A.B. Joosten. et al. Oxidized low-density lipoprotein induces long-term proinflammatory cytokine production and foam cell formation via epigenetic reprogramming of monocytes. Arterioscler. Thromb. Vasc. Biol., 2014, 34, 1731–1738.
5. F.M. van der Valk, S. Bekkering, J. Kroon, et al. Oxidized phospholipids on lipoprotein(a) elicit arterial wall inflammation and an inflammatory monocyte response in humans. Circulation, 2016, 134, 611–624.
6. I. Staprans, X.M. Pan, J.H. Rapp, et al. Oxidized cholesterol in the diet is a source of oxidized lipoproteins in human serum. Journal of Lipid Research, 2003, 44, 705-715.
7. Nutrition in the prevention and treatment of disease. Jose.M. Ordovas, 2001, p157-182.
Western diet can induce trained immunity
According to the definition by scientists in the immunity field, the Western style of living includes consumption of a Western-type diet and sedentary behaviour. The Western-type diet, particularly the American diet, contains high calories and is rich in sugars, trans and saturated fats, salt and food additives, but low in complex carbohydrates, fibre, vitamins and minerals.2
In a study aimed at finding out if the Western-type diet can induce trained immunity, mice which were genetically modified so that they are prone to atherosclerosis, had high expression of genes related to inflammation and #epigenetic reprogramming in their circulating monocytes and their bone marrow myeloid progenitor cells, after being constantly fed with Western-type diet for 4 weeks. This shows that the Western-type diet induces systemic inflammation and long-lasting innate immune cell reprogramming, which amplifies responses to a secondary immune challenge.3
Even after the mice had been switched to a standard normal diet for another 4 weeks, and the serum cholesterol levels and systemic inflammatory markers returned back to normal, the functional reprogramming in myeloid cells still remained.3 The induction in innate immunity response remaining high indicates that the long-lasting reprogramming of the innate cells triggered by the previous Western-type diet could potentially contribute to chronic inflammatory diseases.
Key substances in a Western-type diet that induce trained immunity
Thus far, research studies have identified several @endogenous triggers of innate immunity. These include $lipoprotein(a) and %oxidized low-density lipoprotein.4,5 These studies found that oxidized low-density lipoprotein induces long-term cytokine production which promotes inflammation, and foam cell formation which is associated with atherosclerosis. The long-term cytokine production and foam cell formation are induced via epigenetic reprogramming of monocytes.
When &oxidized cholesterol in the diet is absorbed, it contributes to the pool of oxidized lipoprotein in human serum.6 The high fat Western-type diet thus provides a rich source of endogenous stimulation in form of oxidized low-density lipoprotein that can cause chronic inflammation by triggering a long-lasting innate immunity response via cellular reprogramming.
How does the Western-type diet cause the innate immunity to "memorize"?
The same research study which used mice models to demonstrate the triggering of long-lasting innate immunity by a chronic Western-type diet found that such a diet activates NLRP3 inflammasome, a key innate immune sensor for many environmental danger signals such as uric acid and cholesterol crystals, to induce system inflammation and reprogramming of innate immunity. Therefore, the Western-type diet appears to be mistakenly recognized by the immune system as a threat to the organism.3
What we can learn from these findings?
It is well established that diet high in fat and cholesterol is a risk factor for the development of atherosclerosis, and also for the development of other chronic inflammatory diseases, such as type 2 diabetes, obesity, and chronic liver disease. However, the above studies provide clear evidence that such a diet is mistakenly recognized by innate immunity as a danger signal. The persistent uptake of such a diet could contribute to chronic inflammatory reaction by triggering a long-lasting innate immunity.
Moreover, the fact that studies have shown the reprogramming of innate immune cells occurs via a change in the DNA chromatin level, has caused the emerging concept that ancestral environments and abnormal changes in body functions which are the causes, consequences, or concomitants of disease processes, can be transferred down through generations.
Are the findings from these studies powerful enough to make you determined to make changes to your diet?
*Sterile inflammation: A form of pathogen-free inflammation. This can be caused by mechanical trauma, stress, or environmental conditions. The sterile inflammation referred to in this post is caused by a Western-type diet. These damage-related stimuli induce the secretion of molecular agents, collectively termed danger-associated molecular patterns.
#Epigenetic reprogramming: A process that involves changing of methylation status of histones on the DNA's chromatin level. This results in a change of chromatin structure and hence of gene expression. Epigenetic reprogramming in innate immune cells usually results in the changing of expression of different inflammatory related genes. The change is reversible but usually can last for a few years. Therefore the epigenetic reprogramming in innate immune cells enables the cells to remember the stimulation and react more quickly next time. However, this can also cause chronic inflammation if the innate immune cells are persistently stimulated.
@Endogenous triggers: Stimuli from substances inside the body. In this post, these include lipoprotein(a) and oxidized low-density lipoprotein.
$Lipoprotein(a): This is a plasma lipoprotein composed of apolipoprotein(a) and apolipoprotein B-100 of a low-density lipoproteins-like particle. Lipoproteins are macromolecular complexes of lipid (cholesterol) and proteins that originate mainly from the liver and intestine, and are involved in the transport and redistribution of lipids (cholesterol) in the body.7 In other words, cholesterol travels through the blood on lipoproteins.
%Oxidized low-density lipoprotein: This is a product of chemical reactions between normal low-density lipoproteins and free radicals. It is potentially harmful, because a high level of low-density lipoprotein can lead to a build-up of cholesterol in arteries, which can cause blockages.
&Oxidized cholesterols: They are mainly generated by frying, heating, and processing of a high cholesterol, fat-rich diet.
References
1. M.G. Netea, J. Dominguez-Andres, L.B. Barreiro, et al. Defining trained immunity and its role in health and disease. Nat. Rev. Immunol., 2020, Jun;20(6): 375-388.
2. A. Christ, & E. Latz. The Western lifestyle has lasting effects on metaflammation. Nat. Rev. Immunol., 2019, 19, 267-268.
3. A. Christ, P. Gunther, M.A.R. Lauterbach, et al. Western diet triggers NLRP3-dependent innate immune reprogramming. Cell, 2018, 172, 162-175.
4. S. Bekkering, J. Quintin, L.A.B. Joosten. et al. Oxidized low-density lipoprotein induces long-term proinflammatory cytokine production and foam cell formation via epigenetic reprogramming of monocytes. Arterioscler. Thromb. Vasc. Biol., 2014, 34, 1731–1738.
5. F.M. van der Valk, S. Bekkering, J. Kroon, et al. Oxidized phospholipids on lipoprotein(a) elicit arterial wall inflammation and an inflammatory monocyte response in humans. Circulation, 2016, 134, 611–624.
6. I. Staprans, X.M. Pan, J.H. Rapp, et al. Oxidized cholesterol in the diet is a source of oxidized lipoproteins in human serum. Journal of Lipid Research, 2003, 44, 705-715.
7. Nutrition in the prevention and treatment of disease. Jose.M. Ordovas, 2001, p157-182.
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