Metabolic Control of Smoldering Neuroinflammation

Peruzzotti-Jametti, ﻿Luca; Willis, Cory M.; Hamel, Regan; Krzak, Grzegorz; Pluchino, ﻿Stefano

doi:10.3389/fimmu.2021.705920

Cited by 29 publications

(21 citation statements)

References 182 publications

(245 reference statements)

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“…Studying the processes of immunometabolism in the context of neuroinflammation is a current task of the field as the impact of metabolic changes on immune cells found in the CNS and remains largely undescribed. 24 A number of studies also focus on autophagy as central metabolic pathway in neurodegenerative disorders. 43 Of note, rapamycin as mTOR inhibitor and potent inducer of autophagy showed favourable effects in the EAE model for MS 44 , 45 , 46 , 47 as well with RRMS patients.…”

Section: Discussionmentioning

confidence: 99%

Differential expression of CD8 defines phenotypically distinct cytotoxic T cells in cancer and multiple sclerosis

Burkard

Juan

Dreis

et al. 2022

Clinical & Translational Med

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Background Cytotoxic T lymphocytes take on a leading role in many immune‐related diseases. They function as key effector immune cells fighting cancer cells, but they are also considerably involved in autoimmune diseases. Common to both situations, CD8 + T cells need to adapt their metabolism and effector function to the harsh and nutrient‐deprived conditions of the disease‐associated microenvironment. Methods We used an in vitro starvation as well as rapamycin treatment protocol mimicking nutrient deprivation to generate CD8 Low versus CD8 High T cells and performed FACS‐Sorting followed by transcriptomic profiling of the cytotoxic T cell subsets. Prominent markers identified in the CD8 Low versus the CD8 High T cells were then used to investigate the presence of these cell subsets in immune‐related human diseases. Employing cancer tissue microarrays and PhenOptics multispectral imaging as well as flow cytometry, we studied these CD8 + T cell subsets in cancer and relapsing‐remitting multiple sclerosis patients. Results Starvation induced a decreased expression of CD8, yielding a CD8 Low T cell subpopulation with an altered transcriptomic signature and reduced effector function. CD8 Low T cell showed enhanced ST2L and IL6ST (CD130) expression compared to CD8 High T cells which expressed elevated KLRD1 (CD94) and granzyme B levels within the tumour microenvironment (TME). Spatial analysis revealed the presence of CD8 High T cells in close proximity to tumour cells, while the CD8 Low T cells resided at the tumour boundaries. Importantly, the number of tumour‐infiltrating CD8 Low T lymphocytes correlated with a poor prognosis as well as with enhanced cancer progression in human mammary carcinoma. We also found a reduced frequency of CD8 Low T lymphocytes in a cohort of relapse (disease active) multiple sclerosis patients compared to healthy subjects during immune cell starvation in vitro. Conclusions In summary, our data show that functionally distinct cytotoxic T lymphocytes can be identified based on their expression of CD8. Indicating a more general role in CD8 T cell immunity, these cells may play opposing roles in the TME, and also in the pathophysiology of autoimmune diseases such as multiple sclerosis.

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Section: Discussionmentioning

confidence: 99%

Differential expression of CD8 defines phenotypically distinct cytotoxic T cells in cancer and multiple sclerosis

Burkard

Juan

Dreis

et al. 2022

Clinical & Translational Med

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“…Díaz-Bulnes and colleagues have discovered that macrophage activation and polarization are closely linked with metabolic rewiring (Díaz-Bulnes et al, 2020). Specifically, the metabolism in macrophages changes, depending on whether they are under physiologic or stressed conditions (Peruzzotti-Jametti et al, 2021). Under physiologic conditions, cells use oxidative metabolism and the tricarboxylic acid (TCA) cycle.…”

Section: The Intracellular Networkmentioning

confidence: 99%

A Sedentary and Unhealthy Lifestyle Fuels Chronic Disease Progression by Changing Interstitial Cell Behaviour: A Network Analysis

Huston

2022

Front. Physiol.

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Managing chronic diseases, such as heart disease, stroke, diabetes, chronic lung disease and Alzheimer’s disease, account for a large proportion of health care spending, yet they remain in the top causes of premature mortality and are preventable. It is currently accepted that an unhealthy lifestyle fosters a state of chronic low-grade inflammation that is linked to chronic disease progression. Although this is known to be related to inflammatory cytokines, how an unhealthy lifestyle causes cytokine release and how that in turn leads to chronic disease progression are not well known. This article presents a theory that an unhealthy lifestyle fosters chronic disease by changing interstitial cell behavior and is supported by a six-level hierarchical network analysis. The top three networks include the macroenvironment, social and cultural factors, and lifestyle itself. The fourth network includes the immune, autonomic and neuroendocrine systems and how they interact with lifestyle factors and with each other. The fifth network identifies the effects these systems have on the microenvironment and two types of interstitial cells: macrophages and fibroblasts. Depending on their behaviour, these cells can either help maintain and restore normal function or foster chronic disease progression. When macrophages and fibroblasts dysregulate, it leads to chronic low-grade inflammation, fibrosis, and eventually damage to parenchymal (organ-specific) cells. The sixth network considers how macrophages change phenotype. Thus, a pathway is identified through this hierarchical network to reveal how external factors and lifestyle affect interstitial cell behaviour. This theory can be tested and it needs to be tested because, if correct, it has profound implications. Not only does this theory explain how chronic low-grade inflammation causes chronic disease progression, it also provides insight into salutogenesis, or the process by which health is maintained and restored. Understanding low-grade inflammation as a stalled healing process offers a new strategy for chronic disease management. Rather than treating each chronic disease separately by a focus on parenchymal pathology, a salutogenic strategy of optimizing interstitial health could prevent and mitigate multiple chronic diseases simultaneously.

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“…In acute diseases (such as infections, brain ischemia, or trauma), inflammation promotes acute neurodegenerative processes (Iadecola and Anrather, 2011 ) and sustained inflammation is thought to be a major factor responsible for cognitive decline. In chronic disorders (including neurodegenerative and neuropsychiatric disorders), a subtle and persistent grade of neuroinflammation induces long-lasting neurodegenerative sequelae that ultimately compromise brain functioning (Peruzzotti-Jametti et al, 2021 ).…”

mentioning

confidence: 99%