My last blog post explained that trained immunity, or innate immune memory, provides non-specific protection from secondary infections. The induction of cellular reprogramming in innate immune cells confers an innate immunity with memory characteristics. So far, the only trigger of innate immune memory that we have discussed is microbial triggering, such as triggering from a live attenuated vaccine. But actually the same mechanism of recognition and memory function can also recognize other substances which are not pathogens. In other words, the memory characteristic of the innate immunity mechanism can also be induced by exogenous and endogenous stimuli which are not pathogenic. The fact that trained innate immunity evolved this way, however, does result in harmful effects. Let us have a look at the most recent review paper jointly written by Prof Mihai Netea, who discovered the trained immunity, and the other experts in the field.1
Netea et al suggested that the reprogramming of the innate immunity and the concomitant increased inflammatory responses to exogenous or endogenous stimuli may have harmful consequences. The induction of trained innate immunity can turn a transient inflammation into a long-lasting effect. Prolonged inflammation is associated with several inflammatory diseases, such as atherosclerosis, and neurodegenerative diseases such as Alzheimer's and dementia, and can also lead to tumour growth and metastasis. The review paper provides evidence from research studies for the association between the innate immunity and the above-mentioned diseases.
Atherosclerosis
Atherosclerosis can lead to heart attack and stroke. Persistent inflammation of vessel wall is characteristic of atherosclerosis. Foam cells, which derived from macrophage*, form a plaque which plays a central role in inflammation during all phases of the atherosclerosis.
A study from Prof Netea found that when *monocytes, an innate immune cell, are stimulated by various micro-organisms, they can develop into *macrophages with persistent ability to promote inflammation, to produce cytokine production and form into foam cells which could lead to atherosclerosis. The stimulated monocytes in the experiment were found to have change at the DNA chromatin level, an indication of the trained immunity process.2 The above study indicates that trained immunity stimulated by infections can lead to atherosclerosis.
Alzheimer's disease
Alzheimer's disease is a type of dementia caused by the degeneration of brain cells that process, store and retrieve information, to the point of a loss of function. The disease is characterized by plaques composed of a neurotoxin called β-amyloid. It is hypothesised that the aggregation of the β-amyloid disrupts cell-to-cell communication and activates innate immune cells such as microglia, macrophages which reside in the brain. These immune cells trigger inflammation and ultimately destroy the brain cells.3
In a research study cited by the review, scientists found that peripheral application of inflammatory stimuli in a 3-month old mouse model of Alzheimer's disease, and the second stimulation from β-amyloid plaques at 6-month old leads to a higher β-amyloid plaque load. This indicates a long-lasting training result of microglia.4 Moreover, the scientists also found that the functional changes of microglia are accompanied by reprogramming of the cells. This is evidenced by chromatin changes at HIF1α, a gene which usually responds to peripheral trained immunity.4,5
Cerebral small vessel disease
Cerebral small vessel disease links to systemic inflammation and is a major cause of dementia. According to a research finding cited by the review, in patients with cerebral small vessel disease, peripheral blood-derived monocytes (one type of innate immune cells) have enhanced IL-6 and IL-8 production after **ex vivo stimulation of monocytes with Pam3Cys. Enhanced IL-6 production in the subsequent stimulation is an indication of trained immunity. This shows that the trained immunity contributes to the progression of the disease.6 However, a causal link to the pathophysiology of the small vessels in the brain remains to be determined.
Alzheimer's disease and cerebral small vessel disease associated dementia are neurodegenerative diseases occurring generally in older people. In fact, more evidence suggests that there is a link between trained immunity and the inflammatory condition related to an ageing immune system. Therefore, the review suggested that a better understanding of the dark side of trained immunity in ageing populations might help to fight chronic inflammatory diseases such as dementia in elderly patients.
Tumour growth and metastasis
According to the review, chronic inflammation can provide fuels to sustain disease progression and neoplastic transformation, in particular tumour entities. Studies found that trained immunity and the metabolic processes in cancer cells are both reliant on glycolytic metabolism and the up-regulation of the expression and activity of transcription factors such as HIF1α. These findings provide the basis for the interplay between trained immunity and the tumour cells.
Moreover, the review mentioned that innate immune cells infiltrating the tumours' microenvironments can undergo a reprogramming process that leads to the development of maintained inflammatory responses that can boost up the infection-associated proliferation of lymphocytes, impair apoptosis, promote mitochondrial dysfunction and increase oxidative stress. This ultimately promotes the progression of the tumour. Trained cells produce cytokines such as IL-6 and tumour necrosis factor (TNF) that are associated with increased tumorigenicity and the spread of metastases in specific types of tumours. These include oral squamous cell carcinoma and lung, kidney and breast cancer.7,8
On the other hand, the review mentioned that innate immune cells can be reprogrammed by tumour cells to acquire a more anti-inflammatory situation. This can be exemplified by the low levels of cytokine production in monocytes from chronic lymphocytic leukaemia patients.9 Cancer cells also produce a series of soluble mediators that can induce direct epigenetic and metabolic reprogramming in immune cells and can in turn contribute to the progression of the tumour.10
Conclusion
The reprogramming of the innate immune cells is beneficial when trained immunity results in a fast response to the heterologous pathogen with similar molecular characteristics as the first stimuli. However, from the above examples, we can see that innate immune cells can also be harmful. The resulting prolonged inflammation may also lead to various chronic inflammatory related diseases.
* Monocytes and macrophages are mononuclear cells composing innate immunity. Monocytes are bone-marrow derived leukocytes that circulate in the blood and spleen. Once recruited to tissues, monocytes can differentiate into macrophages and dendritic cells. Macrophages are generally considered terminally-differentiated cells that "engulf" pathogens or toxins and secrete chemokines to recruit other immune cells. The engulfed pathogen is processed by the macrophage and presented to the adaptive immune cells such as B lymphocytes. ** Ex vivo refers to experiments done in cells or tissue from an organism in an external environment with minimal alteration of natural conditions. In the experiment mentioned, the ex vivo stimulation of monocytes were achieved by first isolation of monocytes from blood samples.
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. J. Leentjens, S. Bekkering, L.A.B. Joosten, et al. Trained innate immunity as a novel mechanism linking infection and the development of atherosclerosis. Circ. Res., 2018,122, 664-669.
3. Beta-amyloid and the amyloid hypothesis. Alzheimer's Association. https://www.alz.org/national/documents/topicsheet_betaamyloid.pdf
4. A.C. Wendeln, K. Degenhardt, L. Kaurani, et al. Innate immune memory in the brain shapes neurological disease hallmarks. Nature, 2018, 556, 332-338.
5. S.C. Cheng, J. Quintin, R.A. Cramer, et al. mTOR- and HIF-1-mediated aerobic glycolysis as metabolic basis for trained immunity. Science, 2014, 345, 1250684-1250684.
6. M.P. Noz, A. tel Telgte, K. Wiegertjes, et al. Trained immunity characteristics are associated with progressive cerebral small vessel disease. Stroke, 2018, 49, 2910-2917.
7. S.H. Lee, H.S. Hong, Z.X. Liu, et al. TNFα enhances cancer stem cell-like phenotype via Notch-Hes1 activation in oral squamous cell carcinoma cells. Biochem. Biophys. Res. Commun., 2012, 424, 58-64.
8. D.R. Hodge, E.M. Hurt, & W.L. Farrar. The role of IL-6 and STAT3 in inflammation and cancer. Eur. J. Cancer, 2005, 41, 2502-2512. 9. T. Jurado-Camino, R. Cordoba, L. Esteban-Burgos, et al. Chronic lymphocytic leukemia: a paradigm of innate immune cross-tolerance. J. Immunol., 2015, 194, 719-727.
10. K. Rabold, M.G. Netea, G.J. Adema, et al. Cellular metabolism of tumor-associated macrophages-functional impact and consequences. FEBS Lett., 2017, 591, 3022-3041.
Netea et al suggested that the reprogramming of the innate immunity and the concomitant increased inflammatory responses to exogenous or endogenous stimuli may have harmful consequences. The induction of trained innate immunity can turn a transient inflammation into a long-lasting effect. Prolonged inflammation is associated with several inflammatory diseases, such as atherosclerosis, and neurodegenerative diseases such as Alzheimer's and dementia, and can also lead to tumour growth and metastasis. The review paper provides evidence from research studies for the association between the innate immunity and the above-mentioned diseases.
Atherosclerosis
Atherosclerosis can lead to heart attack and stroke. Persistent inflammation of vessel wall is characteristic of atherosclerosis. Foam cells, which derived from macrophage*, form a plaque which plays a central role in inflammation during all phases of the atherosclerosis.
A study from Prof Netea found that when *monocytes, an innate immune cell, are stimulated by various micro-organisms, they can develop into *macrophages with persistent ability to promote inflammation, to produce cytokine production and form into foam cells which could lead to atherosclerosis. The stimulated monocytes in the experiment were found to have change at the DNA chromatin level, an indication of the trained immunity process.2 The above study indicates that trained immunity stimulated by infections can lead to atherosclerosis.
Alzheimer's disease
Alzheimer's disease is a type of dementia caused by the degeneration of brain cells that process, store and retrieve information, to the point of a loss of function. The disease is characterized by plaques composed of a neurotoxin called β-amyloid. It is hypothesised that the aggregation of the β-amyloid disrupts cell-to-cell communication and activates innate immune cells such as microglia, macrophages which reside in the brain. These immune cells trigger inflammation and ultimately destroy the brain cells.3
In a research study cited by the review, scientists found that peripheral application of inflammatory stimuli in a 3-month old mouse model of Alzheimer's disease, and the second stimulation from β-amyloid plaques at 6-month old leads to a higher β-amyloid plaque load. This indicates a long-lasting training result of microglia.4 Moreover, the scientists also found that the functional changes of microglia are accompanied by reprogramming of the cells. This is evidenced by chromatin changes at HIF1α, a gene which usually responds to peripheral trained immunity.4,5
Cerebral small vessel disease
Cerebral small vessel disease links to systemic inflammation and is a major cause of dementia. According to a research finding cited by the review, in patients with cerebral small vessel disease, peripheral blood-derived monocytes (one type of innate immune cells) have enhanced IL-6 and IL-8 production after **ex vivo stimulation of monocytes with Pam3Cys. Enhanced IL-6 production in the subsequent stimulation is an indication of trained immunity. This shows that the trained immunity contributes to the progression of the disease.6 However, a causal link to the pathophysiology of the small vessels in the brain remains to be determined.
Alzheimer's disease and cerebral small vessel disease associated dementia are neurodegenerative diseases occurring generally in older people. In fact, more evidence suggests that there is a link between trained immunity and the inflammatory condition related to an ageing immune system. Therefore, the review suggested that a better understanding of the dark side of trained immunity in ageing populations might help to fight chronic inflammatory diseases such as dementia in elderly patients.
Tumour growth and metastasis
According to the review, chronic inflammation can provide fuels to sustain disease progression and neoplastic transformation, in particular tumour entities. Studies found that trained immunity and the metabolic processes in cancer cells are both reliant on glycolytic metabolism and the up-regulation of the expression and activity of transcription factors such as HIF1α. These findings provide the basis for the interplay between trained immunity and the tumour cells.
Moreover, the review mentioned that innate immune cells infiltrating the tumours' microenvironments can undergo a reprogramming process that leads to the development of maintained inflammatory responses that can boost up the infection-associated proliferation of lymphocytes, impair apoptosis, promote mitochondrial dysfunction and increase oxidative stress. This ultimately promotes the progression of the tumour. Trained cells produce cytokines such as IL-6 and tumour necrosis factor (TNF) that are associated with increased tumorigenicity and the spread of metastases in specific types of tumours. These include oral squamous cell carcinoma and lung, kidney and breast cancer.7,8
On the other hand, the review mentioned that innate immune cells can be reprogrammed by tumour cells to acquire a more anti-inflammatory situation. This can be exemplified by the low levels of cytokine production in monocytes from chronic lymphocytic leukaemia patients.9 Cancer cells also produce a series of soluble mediators that can induce direct epigenetic and metabolic reprogramming in immune cells and can in turn contribute to the progression of the tumour.10
Conclusion
The reprogramming of the innate immune cells is beneficial when trained immunity results in a fast response to the heterologous pathogen with similar molecular characteristics as the first stimuli. However, from the above examples, we can see that innate immune cells can also be harmful. The resulting prolonged inflammation may also lead to various chronic inflammatory related diseases.
* Monocytes and macrophages are mononuclear cells composing innate immunity. Monocytes are bone-marrow derived leukocytes that circulate in the blood and spleen. Once recruited to tissues, monocytes can differentiate into macrophages and dendritic cells. Macrophages are generally considered terminally-differentiated cells that "engulf" pathogens or toxins and secrete chemokines to recruit other immune cells. The engulfed pathogen is processed by the macrophage and presented to the adaptive immune cells such as B lymphocytes. ** Ex vivo refers to experiments done in cells or tissue from an organism in an external environment with minimal alteration of natural conditions. In the experiment mentioned, the ex vivo stimulation of monocytes were achieved by first isolation of monocytes from blood samples.
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. J. Leentjens, S. Bekkering, L.A.B. Joosten, et al. Trained innate immunity as a novel mechanism linking infection and the development of atherosclerosis. Circ. Res., 2018,122, 664-669.
3. Beta-amyloid and the amyloid hypothesis. Alzheimer's Association. https://www.alz.org/national/documents/topicsheet_betaamyloid.pdf
4. A.C. Wendeln, K. Degenhardt, L. Kaurani, et al. Innate immune memory in the brain shapes neurological disease hallmarks. Nature, 2018, 556, 332-338.
5. S.C. Cheng, J. Quintin, R.A. Cramer, et al. mTOR- and HIF-1-mediated aerobic glycolysis as metabolic basis for trained immunity. Science, 2014, 345, 1250684-1250684.
6. M.P. Noz, A. tel Telgte, K. Wiegertjes, et al. Trained immunity characteristics are associated with progressive cerebral small vessel disease. Stroke, 2018, 49, 2910-2917.
7. S.H. Lee, H.S. Hong, Z.X. Liu, et al. TNFα enhances cancer stem cell-like phenotype via Notch-Hes1 activation in oral squamous cell carcinoma cells. Biochem. Biophys. Res. Commun., 2012, 424, 58-64.
8. D.R. Hodge, E.M. Hurt, & W.L. Farrar. The role of IL-6 and STAT3 in inflammation and cancer. Eur. J. Cancer, 2005, 41, 2502-2512. 9. T. Jurado-Camino, R. Cordoba, L. Esteban-Burgos, et al. Chronic lymphocytic leukemia: a paradigm of innate immune cross-tolerance. J. Immunol., 2015, 194, 719-727.
10. K. Rabold, M.G. Netea, G.J. Adema, et al. Cellular metabolism of tumor-associated macrophages-functional impact and consequences. FEBS Lett., 2017, 591, 3022-3041.
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