Myeloid p38 MAPK signaling in intestinal homeostasis, inflammation and tumorigenesis = Señalización por la MAPK p38 de células mieloides en la homeostasis, inflamación y tumorogénesis intestinal

dc.contributor
Universitat de Barcelona. Departament de Biomedicina
dc.contributor.author
Youssif, Catrin
dc.date.accessioned
2018-03-06T10:58:26Z
dc.date.available
2018-10-27T02:00:10Z
dc.date.issued
2017-10-27
dc.identifier.uri
http://hdl.handle.net/10803/462108
dc.description.abstract
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 p38. Specifically, p38 is a key regulator of epithelial cell homeostasis protecting against inflammation-associated colon tumorigenesis in mice. However, the contribution of myeloid p38 to colitis-associated tumorigenesis has been largely neglected. Therefore, the objective of this thesis is to investigate the role of myeloid p38 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 p38 is a key mediator of inflammatory responses, and identify insulin-like growth factor-1 (IGF-1) as a novel effector downstream of p38 signaling in macrophages. To our knowledge, the regulation of IGF-1 by p38 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 p38-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 p38 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 p38 plays important roles in the pathogenesis of inflammatory diseases. In accordance, we observed that p38 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 p38-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 p38 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.
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dc.format.extent
280 p.
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dc.format.mimetype
application/pdf
dc.language.iso
eng
en_US
dc.publisher
Universitat de Barcelona
dc.rights.license
ADVERTIMENT. L'accés als continguts d'aquesta tesi doctoral i la seva utilització ha de respectar els drets de la persona autora. Pot ser utilitzada per a consulta o estudi personal, així com en activitats o materials d'investigació i docència en els termes establerts a l'art. 32 del Text Refós de la Llei de Propietat Intel·lectual (RDL 1/1996). Per altres utilitzacions es requereix l'autorització prèvia i expressa de la persona autora. En qualsevol cas, en la utilització dels seus continguts caldrà indicar de forma clara el nom i cognoms de la persona autora i el títol de la tesi doctoral. No s'autoritza la seva reproducció o altres formes d'explotació efectuades amb finalitats de lucre ni la seva comunicació pública des d'un lloc aliè al servei TDX. Tampoc s'autoritza la presentació del seu contingut en una finestra o marc aliè a TDX (framing). Aquesta reserva de drets afecta tant als continguts de la tesi com als seus resums i índexs.
dc.source
TDX (Tesis Doctorals en Xarxa)
dc.subject
Gastroenterologia
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dc.subject
Gastroenterología
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dc.subject
Gastroenterology
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dc.subject
Tumors
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dc.subject
Tumores
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dc.subject
Inflamació
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dc.subject
Inflamación
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dc.subject
Inflammation
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dc.subject.other
Ciències Experimentals i Matemàtiques
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dc.title
Myeloid p38 MAPK signaling in intestinal homeostasis, inflammation and tumorigenesis = Señalización por la MAPK p38 de células mieloides en la homeostasis, inflamación y tumorogénesis intestinal
en_US
dc.type
info:eu-repo/semantics/doctoralThesis
dc.type
info:eu-repo/semantics/publishedVersion
dc.subject.udc
616
en_US
dc.contributor.director
Rodríguez Nebreda, Ángel
dc.contributor.director
Comalada Vila, Mònica
dc.contributor.tutor
Tauler Girona, Albert
dc.embargo.terms
12 mesos
en_US
dc.rights.accessLevel
info:eu-repo/semantics/openAccess


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