Papel de los DAMPs mitocondriales en la generación de tolerancia cruzada en macrófagos estudio en pacientes de Síndrome Coronario Agudo

• Autores: Irene Fernández Ruiz
• Directores de la Tesis: Francisco Arnalich Fernández (dir. tes.), Eduardo López-Collazo (dir. tes.)
• Lectura: En la Universidad Autónoma de Madrid ( España ) en 2012
• Idioma: español
• Tribunal Calificador de la Tesis: Lisardo Boscá (presid.), Francisco García Río (secret.), Melchor Álvarez de Mon Soto (voc.), Pablo Fuentes Prior (voc.), Rosa del Campo Moreno (voc.)
• Materias:
  • Ciencias de la vida
    • Inmunología
• Enlaces
  • Tesis en acceso abierto en: digitool-uam.greendata.es
• Resumen

  • The immune system contributes to the development and progression of Acute Coronary Syndromes (ACS) and thus, the functional behavior of immune cells is of great interest in this context. However, little is known regarding the potential counterbalancing role of anti-inflammatory responses. Here, we report that peripheral blood mononuclear cells from STEMI patients show a gene expression profile 24-36h after MI that supports a shift to a negative regulation of lymphocytes and macrophages compared with patients with no MI (unstable angina (UA)). We also found that M¿ from STEMI and NSTEMI patients showed an anti-inflammatory M2 phenotype 24-36h after MI compared with UA and healthy volunteers (HV). On the other hand, depending on the activation potential of the M¿, LPS stimulation can induce an M1 or M2 response. In this context, not only M¿ from MI patients were shifted towards the M2 activation, but also 27 out of 45 patients (STEMI and NSTEMI) showed M¿ endotoxin tolerance after LPS stimulation, whereas none of the 30 patients with UA showed this state.

    In most of the cases, the endotoxin tolerance has been associated to a previous contact with the endotoxin, which induces a refractory state to a second endotoxin challenge. However, in our cohort of patients there were no previous infections which could account for the observed tolerant state. On the other hand, endogenous ligands released by damaged tissues are known to activate TLR signaling as well as induce endotoxin tolerance-like features. Indeed, we found that levels of serum mitochondrial DNA (mtDNA) were significantly higher in STEMI patients, the patients with higher tissue damage. Interestingly, the endotoxin tolerance is more profound in STEMI than in NSTEMI patients. In this context, mitochondrial antigens such as mtDNA, induce M¿-mediated responses and, therefore, could be implicated in the generation of endotoxin tolerance observed in these patients. Indeed, we found that exposition of human M¿ to mtDNA or whole mitochondrial lysates induced endotoxin tolerance in vitro. This cross-tolerance to TLR4 was characterized by a decreased production of pro-inflammatory cytokines, increased production of anti-inflammatory factors, increased frequency of the M2-marker CD163, significant over-expression of IRAK-M and lower levels of antigen presenting molecules after LPS stimulation. Furthermore, mitochondrial DAMPs also induced a partial cross-tolerance to TLR2, whereas signaling through TLR3 was not affected.

    As M¿ play a crucial role in the inflammatory response and the subsequent state of tolerance, these endogenous ligands may contribute to clinical complications in ACS. Furthermore, the incidence of endotoxin tolerance is associated with a higher risk of secondary infections. In this context, 7 out of the 45 patients with MI (4 STEMI and 3 NSTEMI) reported an infection in the next three months after the coronary episode. The higher rate of infection correlated with the endotoxin tolerance in M¿ from MI patients.