The role of chemokine (c-c motif) ligand 2 in inflammation, oxidative stress, aging and metabolism
- Autores: Fedra Nicaury Luciano Mateo
- Directores de la Tesis: José Luis Domingo Roig (dir. tes.), Jorge Joven Maried (dir. tes.)
- Lectura: En la Universitat Rovira i Virgili ( España ) en 2019
- Idioma: español
- Tribunal Calificador de la Tesis: Manuel Castro Cabezas (presid.), Raul V. Duran Díaz (secret.), Meritxell Arenas Prat (voc.)
- Programa de doctorado: Programa de Doctorado en Biomedicina por la Universidad Rovira i Virgili
- Materias:
- Enlaces
- Tesis en acceso abierto en: TDX
- Resumen
Metabolism and immune system are closely interconnected and their interactions play an important role in whole-body homeostasis. This emerging idea has provided the new concept of immunometabolism. Immunometabolism has been separated into two main arms: cellular and tissue immunometabolism. Tissue immunometabolism, one of the main aspects of this thesis, focalizes on how immune cells can regulate the tissue metabolism with the aim to induce adaptation to environmental challenges. When cellular adaptation fails, and malfunction becomes extreme, additional leukocytes are recruited to help the tissue to adapt to these particular stress condition. For instance, during an infection, an increase of neutrophils and other immune cells involved in acute inflammation has been observed. The activation, proliferation, differentiation and polarization of these immune cells represent significant metabolic stress, which can compromise the cellular metabolism, homeostasis and energetic requirements.
The deregulation of immune cells mobilization and chronic metabolic stress promote metabolic abnormalities in non-immune pathologies such as obesity, type 2 diabetes mellitus (T2DM), cardiovascular diseases, neurodegeneration, arteriosclerosis or cancer. Nevertheless, how these changes in the immunological profile affect systemic metabolism are still not clear, although experimental evidence supports an association between immune cell differentiation and tissue metabolic reprogramming. These alterations affect the most important nutrient-sensing pathways as AMP-activate protein kinase (AMPK) and mammalian target of rapamycin (mTOR) pathway, which play a critical role in the generation of these chronic conditions.
On the other hand, tissue metabolic reprogramming cannot be limited to local effects. The alteration of metabolic tissues such as liver, muscle and adipose tissue can induce systemic metabolic disturbances, which can affect the general homeostasis and cause a vicious cycle of inflammation.
The main problem of tissue immunometabolism is when cellular adaptation is not possible. In this extreme condition cells die, and systemic metabolism can be compromised. All these conditions give place to metabolic pathologies as insulin resistance, T2DM, liver steatosis and cardiovascular diseases. Growing evidences support that chemokines play a crucial role in all these processes. Specially, the increase of chemokine C-C motif ligand 2 (CCL2) in metabolic diseases suggests the possibility of this chemokine to play a systemic role in the regulation of metabolism. The key question is if increase of CCL2 is the cause or consequence of the problem.
For this reason, we explored the effect of CCL2 ablation in the metabolism of mice with an important background of hyperlipidemia, hepatic steatosis and metabolic syndrome. In addition, we investigated whether that effect might be conditioned by diet. Obtained results are presented in the first study. Our results denoted that CCL2 ablation could be a therapeutic target especially in non-alcoholic fatty liver disease (NAFLD) development. In CCL2 deficient mice the histologic alterations and fatty liver disease were abrogated. Moreover, we observed an improvement in oxidative stress and inflammation. All these alterations were associated with a normalization of metabolic disturbances and an increase of selective autophagy.
Obtained results open a brief to other questions. For example, does CCL2 function go further to its chemoattracting capacity? Can this chemokine affect the systemic energy metabolism? To answer these questions, we generated targeted CCL2 cisgenic mice, which overexpressed CCL2 in all tissues and results are presented in study 2. We explored different metabolic tissues and results confirmed that CCL2 overexpression have a drastic effect in liver and especially in muscle metabolism. Unlike CCL2 deficiency, CCL2 overexpression was associated with hepatic steatosis and an increase in liver alterations markers. All our results, together with important metabolic alterations, suggest an inefficient liver ATP synthesis. Contrarily, these animals showed considerable muscle fragility, together with a hyperactivation of catabolic pathways. These results suggest that the effect of CCL2 overexpression is tissue-dependent.
In study 3 we evaluated the effect of CCL2 overexpression in a mice model of Hutchinson-Gilford progeria syndrome, a model of accelerated aging. These mice have the capacity to develop all metabolic alterations associated to aging such as sarcopenia, lipodystrophy, insulin resistance, cardiovascular alterations, cachexia, oxidative stress, mitochondrial dysfunction and cellular senescence. Our results demonstrate that overexpression of CCL2 promotes the systemic alterations in Hutchinson-Gilford progeria mice, which developed general fibrosis and metabolic alterations leading to accelerated aging.
The finding of therapeutic targets for the treatment of metabolic diseases is an important point in current investigations in our research group. The findings of this thesis suggest that CCL2 could be an important therapeutic target in different metabolic diseases.
