Myeloid p38 mapk signaling in intestinal homeostasis, inflammation and tumorigenesis
- Autores: Youssif Catrin
- Directores de la Tesis: Ángel Rodríguez Nebreda (dir. tes.), Mónica Comalada Vila (codir. tes.), Albert Tauler Girona (tut. tes.)
- Lectura: En la Universitat de Barcelona ( España ) en 2017
- Idioma: español
- Tribunal Calificador de la Tesis: Purificacion Muñoz Canoves (presid.), Azucena Salas Martínez (secret.), Vassilis Gorgoulis (voc.)
- Programa de doctorado: Programa de Doctorado en Biomedicina por la Universidad de Barcelona
- Materias:
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- Resumen
Chronic inflammation is a hallmark of colon cancer, and patients with inflammatory bowel disease are prone to developing colon tumors. In recent years, many efforts have been devoted to characterize the interplay between inflammation, the tumor microenvironment and tumorigenesis. However, the molecular and cellular events involved in the pathogenesis of colitis-associated carcinogenesis are not fully understood.
Myeloid cells play a key role in the tumor microenvironment, regulating tumor growth and therapeutic responses. One of the pathways that is often implicated in inflammatory diseases and cancer relies on the protein kinase p38α. Specifically, p38α is a key regulator of epithelial cell homeostasis protecting against inflammation-associated colon tumorigenesis in mice. However, the contribution of myeloid p38α to colitis-associated tumorigenesis has been largely neglected. Therefore, the objective of this thesis is to investigate the role of myeloid p38α in intestinal mucosal repair and its implications in colorectal cancer by performing in vivo assays in mice. We further complemented the in vivo experiments using cellular models.
We observed that mice with myeloid cell-specific downregulation of p38α generate less colon tumors in response to AOM/DSS treatment compared to wild-type mice. Our results extend previous findings indicating that myeloid p38α is a key mediator of inflammatory responses, and identify insulin-like growth factor-1 (IGF-1) as a novel effector downstream of p38α signaling in macrophages. To our knowledge, the regulation of IGF-1 by p38α in macrophages has not been described previously. IGF-1 is a natural growth hormone that is known to have also anti-inflammatory and pro-repair functions. We found that myeloid cells are a major source of IGF-1 in the large intestine, and genetic or pharmacological inhibition of IGF-1 suppresses inflammatory cell recruitment and reduces colitis-associated colon tumor burden.
Ly6ChiCCR2+ monocytes are continuously generated in the bone marrow from hematopoietic stem cells and recruited to healthy and injured tissues, where they give rise to intestinal effector cells. Our studies demonstrate that Ly6ChiCCR2+ monocytes are reduced in p38α-ΔMC mice and IGF-1-ΔMC mice compared to WT mice, even without any treatment. We believe this is important for the observed phenotype, given the key role of inflammatory monocytes in triggering the recruitment of other immune cells as well as in the initiation of the adaptive immune response. Our results indicate that suppression of p38α in myeloid cells ameliorates intestinal inflammation mainly through repression of inflammatory cell recruitment, which in turn results in reduced tumor burden. Several human and mouse studies have demonstrated that the regulation of inflammatory cytokines by p38α plays important roles in the pathogenesis of inflammatory diseases. In accordance, we observed that p38α in myeloid cells positively regulates key inflammatory mediators during intestinal inflammation. However, our results indicate that the decreased levels of inflammatory mediators and IGF-1 observed in DSS-treated p38α-ΔMC mice correlates with a reduced number of infiltrated immune cells.
Currently, the IGF-1 pathway is gaining tremendous interest due to its important role in cancer as well as inflammatory bowel disease, not only by modulating the innate and acquired immune system, but also through its multi-functional involvement in the tumor microenvironment. Our results suggest that targeted inhibition of the p38α pathway in myeloid cells could be therapeutically useful especially in tumors associated with chronic inflammation. Of note, IGF-1 is known to have mitogenic and anti-apoptotic functions, in addition to its role in inflammatory cell recruitment. Therefore, the targeting of extracellular effectors produced by myeloid cells that are implicated in disease pathogenesis such as IGF-1 might overcome the difficulty of targeting specific cell types.
