Impact of genetic and environmental factors in intestinal inflammation
Author: Diaz Perez, Oscar Eduardo
Date: 2021-05-28
Location: Germinal Center Lecture Hall, CMM L8:00
Time: 09.00
Department: Inst för medicin, Solna / Dept of Medicine, Solna
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Thesis (4.536Mb)
Abstract
The gastrointestinal tract, is continuously exposed to a wide variety of stimuli, including dietary-derived metabolites, environmental compounds and the microbiota. Since these antigens can be beneficial or detrimental for the organism, proper sensing of the luminal content is essential for orchestrating both pro-inflammatory and tolerogenic immune responses on demand and therefore, ensure the establishment of intestinal homeostasis. Disruption of these mechanisms might result in inflammation, a characteristic of intestinal disorders, such as inflammatory bowel disease (IBD). How environmental triggers modulate intestinal inflammation in genetically susceptible host leading to IBD is largely unclear. The gap in knowledge around this topic is likely due to the lack of versatile in vivo models allowing the testing of a wide variety of compounds in a cost-effective manner. The aim of my doctoral thesis was to understand how intestinal inflammation is impacted by genetic factors and environmental exposures.
In study I and II we analyzed how the sensing of dietary-derived metabolites modulate immune homeostasis. In study I, we found that retinoic acid receptor a (RARa) signaling in intestinal epithelial cells modulated lineage specification of secretory cells and the development of the intestinal immune system. Epithelial RARa signaling was essential for mounting protective responses against pathogen infection and maintaining intestinal homeostasis. In study II, we explored how combinatorial activation of ligand-activated transcription factors that sense dietary metabolites in vivo modulate cytokine signaling. We found that co-exposure with more than one ligand resulted in activation of the corresponding receptors, and in induction of specific cytokine profiles as a result of their interaction.
In study III, we investigated how GPR35, an IBD-risk gene, modulated intestinal immune homeostasis. We found that Gpr35 deficiency in macrophages resulted in exacerbated colitis, due to low expression of genes involved in corticosterone synthesis and tumor necrosis factor (Tnf). We also identified lysophosphatidic acid as a potential GPR35 ligand that induces Tnf expression in macrophages in a GPR35-dependent manner.
In study IV, we further examined how environmental factors modulate intestinal inflammation and found that perfluorooctane sulfonic acid (PFOS), an environmental pollutant, exacerbates intestinal inflammation. This was associated with impaired epithelial barrier function and systemic T cell responses. Taken together, this doctoral thesis provides insight into how environmental and genetic factors modulate immune responses contributing to the maintenance of intestinal homeostasis.
In study I and II we analyzed how the sensing of dietary-derived metabolites modulate immune homeostasis. In study I, we found that retinoic acid receptor a (RARa) signaling in intestinal epithelial cells modulated lineage specification of secretory cells and the development of the intestinal immune system. Epithelial RARa signaling was essential for mounting protective responses against pathogen infection and maintaining intestinal homeostasis. In study II, we explored how combinatorial activation of ligand-activated transcription factors that sense dietary metabolites in vivo modulate cytokine signaling. We found that co-exposure with more than one ligand resulted in activation of the corresponding receptors, and in induction of specific cytokine profiles as a result of their interaction.
In study III, we investigated how GPR35, an IBD-risk gene, modulated intestinal immune homeostasis. We found that Gpr35 deficiency in macrophages resulted in exacerbated colitis, due to low expression of genes involved in corticosterone synthesis and tumor necrosis factor (Tnf). We also identified lysophosphatidic acid as a potential GPR35 ligand that induces Tnf expression in macrophages in a GPR35-dependent manner.
In study IV, we further examined how environmental factors modulate intestinal inflammation and found that perfluorooctane sulfonic acid (PFOS), an environmental pollutant, exacerbates intestinal inflammation. This was associated with impaired epithelial barrier function and systemic T cell responses. Taken together, this doctoral thesis provides insight into how environmental and genetic factors modulate immune responses contributing to the maintenance of intestinal homeostasis.
List of papers:
I. Jijon HB, Suarez-Lopez L, Diaz OE, Das S, De Calisto J, Parada-kusz M, Yaffe MB, Pittet MJ, Mora JR, Belkaid Y, Xavier RJ, Villablanca EJ. Intestinal epithelial cell-specific RARα depletion results in aberrant epithelial cell homeostasis and underdeveloped immune system. Mucosal Immunology. 2018 May;11(3):703-715.
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II. Diaz OE, Xue S, Luo X, Nava J, Appelblom A, Morales RA, Das S, Villablanca EJ. Retinoic acid induced cytokines are selectively modulated by liver X receptor activation in zebrafish. Reproductive Toxicology. 2020 Apr;93:163-168.
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III. Kaya B, Doñas C, Wuggenig P, Diaz OE, Morales RA, Melhem H; Swiss IBD. Cohort Investigators, Hernández PP, Kaymak T, Das S, Hruz P, Franc Y, Geier F, Ayata CK, Villablanca EJ, Niess JH. Lysophosphatidic Acid-Mediated GPR35 Signaling in CX3CR1+ Macrophages Regulates Intestinal Homeostasis. Cell Reports. 2020 Aug 4;32(5):107979.
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IV. Diaz OE, Sorini C, Das S, Morales RA, Appelblom A, Luo X, Nava J, Frede A, Krais AM, Wincent E, Villablanca EJ. Oral perfluorooctanesulfonic acid enhance neutrophil-mediated intestinal damage and expand systemic T cells during experimental colitis. [Manuscript]
I. Jijon HB, Suarez-Lopez L, Diaz OE, Das S, De Calisto J, Parada-kusz M, Yaffe MB, Pittet MJ, Mora JR, Belkaid Y, Xavier RJ, Villablanca EJ. Intestinal epithelial cell-specific RARα depletion results in aberrant epithelial cell homeostasis and underdeveloped immune system. Mucosal Immunology. 2018 May;11(3):703-715.
Fulltext (DOI)
Pubmed
View record in Web of Science®
II. Diaz OE, Xue S, Luo X, Nava J, Appelblom A, Morales RA, Das S, Villablanca EJ. Retinoic acid induced cytokines are selectively modulated by liver X receptor activation in zebrafish. Reproductive Toxicology. 2020 Apr;93:163-168.
Fulltext (DOI)
Pubmed
View record in Web of Science®
III. Kaya B, Doñas C, Wuggenig P, Diaz OE, Morales RA, Melhem H; Swiss IBD. Cohort Investigators, Hernández PP, Kaymak T, Das S, Hruz P, Franc Y, Geier F, Ayata CK, Villablanca EJ, Niess JH. Lysophosphatidic Acid-Mediated GPR35 Signaling in CX3CR1+ Macrophages Regulates Intestinal Homeostasis. Cell Reports. 2020 Aug 4;32(5):107979.
Fulltext (DOI)
Pubmed
View record in Web of Science®
IV. Diaz OE, Sorini C, Das S, Morales RA, Appelblom A, Luo X, Nava J, Frede A, Krais AM, Wincent E, Villablanca EJ. Oral perfluorooctanesulfonic acid enhance neutrophil-mediated intestinal damage and expand systemic T cells during experimental colitis. [Manuscript]
Institution: Karolinska Institutet
Supervisor: Villablanca, Eduardo J.
Co-supervisor: Harris, Robert A.; Das, Srustidhar
Issue date: 2021-05-07
Rights:
Publication year: 2021
ISBN: 978-91-8016-230-2
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