Role of P38Alpha Kinase in myeloid cells during lung metastasis and inflammation

• Autores: Clara Borras Eroles
• Directores de la Tesis: Ángel Rodríguez Nebreda (dir. tes.), Cubillos Rojas Mónica (codir. tes.), Annabel Fernández Valledor (tut. tes.)
• Lectura: En la Universitat de Barcelona ( España ) en 2023
• Idioma: inglés
• Tribunal Calificador de la Tesis: Ana Cuenda Méndez (presid.), Carlos Sebastian Muñoz (secret.), María Casanova Acebes (voc.)
• Programa de doctorado: Programa de Doctorado en Biomedicina por la Universidad de Barcelona
• Materias:
  • Química
    • Bioquímica
      • Biología molecular
  • Ciencias de la vida
    • Inmunología
  • Ciencias médicas
    • Ciencias clínicas
      • Oncología
    • Patología
      • Patología experimental
• Enlaces
  • Tesis en acceso abierto en: TDX
• Resumen

  • The lungs are constantly exposed to external particles and microbes, so their particular immune environment is immunosuppressive to avoid unnecessary inflammatory responses. This increases the susceptibility of this organ to lung metastasis, a hallmark of advanced cancer constituting an important cause of dead. Among immune cells in tumors, myeloid cells are very predominant and strongly influence the outcome of primary tumours and metastasis. They promote an immunosuppressive environment and several studies indicate that a high infiltration of myeloid cells in tumours correlates with worse prognosis in patients. In the lungs there is a specific type of tissue-resident myeloid cells, alveolar macrophages (AMs), which are crucial for the fitness of the lungs. These cells are found patrolling the alveolar surface and maintain the immune tolerance of the lungs. A tight regulation of the inflammation pathways is central in AMs. Here, we have studied the influence of the stress-activated protein kinase p38alpha in lung myeloid cells to determine its role in lung tumorigenesis. By using a mouse model in which we deleted p38alpha kinase from myeloid cells (p38alpha 1Lys), we observed that those mice presented less lung metastasis, accompanied by an increase in activated T cells. Further transcriptomic analysis allowed us to determine that p38alpha is of particular importance in the biology of AMs, especially in their antigen presentation capacity via the major histocompatibility complex class II (MHCII). In vitro experiments using bone marrow derived macrophages (BMDMs) have allowed us to determine that the regulation of MHCII by p38alpha is through transcriptional regulation of class II transcriptional activator (CIITA). Our results indicate that p38alpha could regulate CIITA by controlling histone deacetylase 6 (HDAC6) through MK2, a key p38alpha substrate. We have also observed that AMs highly depend on p38alpha for other crucial functions such as phagocytosis, efferocytosis and cholesterol homeostasis, processes which were also found affected in AMs from p38alpha1Lys. Additionally, in vivo lung inflammation experiments of asthma and acute lung injury revealed that p38alpha is crucial to maintain lung immunosuppression, a condition which benefits immune evasion of cancer cells. Our results support the importance of a balanced p38alpha signalling both in homeostasis and in different lung inflammatory pathologies.