The Differential Expression of the Inflammasomes in Adipose Tissue and Colon Influences the Development of Colon Cancer in a Context of Obesity by Regulating Intestinal Inflammation
Gema Frühbeck,1– 4,* Amaia Mentxaka,1,2,* Patricia Ahechu,5 Javier Gómez-Ambrosi,1– 3 Beatriz Ramírez,1– 3 Sara Becerril,1– 3 Amaia Rodríguez,1– 3 Xabier Unamuno,1,2,6 Javier A Cienfuegos,5 Marcos Casado,1 María A Burrell,7 Marina Martín,7 Jorge Baixauli,5 Victor Valentí,5 Rafael Mon...
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2021
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inflammasome nlrp inflammation colon cancer obesity adipose tissue akkermansia muciniphila Pathology RB1-214 Therapeutics. Pharmacology RM1-950 |
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inflammasome nlrp inflammation colon cancer obesity adipose tissue akkermansia muciniphila Pathology RB1-214 Therapeutics. Pharmacology RM1-950 Frühbeck G Mentxaka A Ahechu P Gómez-Ambrosi J Ramírez B Becerril S Rodríguez A Unamuno X Cienfuegos JA Casado M Burrell MA Martín M Baixauli J Valentí V Moncada R Reina G Silva C Catalán V The Differential Expression of the Inflammasomes in Adipose Tissue and Colon Influences the Development of Colon Cancer in a Context of Obesity by Regulating Intestinal Inflammation |
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Gema Frühbeck,1– 4,* Amaia Mentxaka,1,2,* Patricia Ahechu,5 Javier Gómez-Ambrosi,1– 3 Beatriz Ramírez,1– 3 Sara Becerril,1– 3 Amaia Rodríguez,1– 3 Xabier Unamuno,1,2,6 Javier A Cienfuegos,5 Marcos Casado,1 María A Burrell,7 Marina Martín,7 Jorge Baixauli,5 Victor Valentí,5 Rafael Moncada,8 Gabriel Reina,9 Camilo Silva,4 Victoria Catalán1– 3 1Metabolic Research Laboratory, Clínica Universidad de Navarra, Pamplona, Spain; 2CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Pamplona, Spain; 3Obesity and Adipobiology Group, Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain; 4Department of Endocrinology & Nutrition, Clínica Universidad de Navarra, Pamplona, Spain; 5Department of Surgery, Clínica Universidad de Navarra, Pamplona, Spain; 6Medical Engineering Laboratory, Clínica Universidad de Navarra, Pamplona, Spain; 7Department of Histology and Pathology, University of Navarra, Pamplona, Spain; 8Department of Anesthesia, Clínica Universidad de Navarra, Pamplona, Spain; 9Microbiology Laboratory, Clínica Universidad de Navarra, Pamplona, Spain*These authors contributed equally to this workCorrespondence: Gema FrühbeckDepartment of Endocrinology, Clínica Universidad de Navarra, Avda. Pío XII, 36, Pamplona, 31008, SpainTel +34 948 25 54 00 (ext. 4484)Email gfruhbeck@unav.esVictoria CatalánMetabolic Research Laboratory, Clínica Universidad de Navarra, Avda. Pío XII, 36, Pamplona, 31008, SpainTel +34 948 25 54 00 (ext. 5133)Email vcatalan@unav.esBackground: Inflammasomes maintain tissue homeostasis and their altered regulation in the colon, and the adipose tissue (AT) leads to chronic activation of inflammatory pathways promoting colon cancer (CC) development. We aimed to analyze the potential involvement of inflammasomes in obesity-associated CC.Methods: Ninety-nine volunteers [61 with obesity (OB) and 38 normoponderal (NP)] further subclassified according to the approved protocol for the diagnosis of CC (58 without CC and 41 with CC) were included in the case–control study.Results: CC (P< 0.01) and obesity (P< 0.01) were accompanied by increased mRNA levels of NLRP3, NLRP6, ASC, IL1B and NOD2 in VAT. Contrarily, patients with CC exhibited a downregulation of NLRP6 and IL18 in their colon. Additionally, we revealed that the decreased Nlrp1 (P< 0.05), Nlrp3 (P< 0.01) and Nlrp6 (P< 0.01) mRNA levels in the colon from obese rats significantly increase (P< 0.05) after caloric restriction. Adipocyte-conditioned media obtained from subjects with obesity reduced (P< 0.01) the mRNA of NLRP3 as well as molecules involved in maintaining the intestinal integrity (MUC2, CLDN1 and TJP1) and the anti-inflammatory factors FGF21, KLF4, and IL33 and in HT-29 cells. We also found that the knockdown of NLRP6 in HT-29 cells significantly upregulated (P< 0.05) the mRNA of NLRP1 and NLRP3 and inhibited (P< 0.05) the expression levels of MUC2. Finally, we showed that the incubation of HT-29 with Akkermansia muciniphila influence (P< 0.05) the inflammasome expression profile as well as intestinal integrity-related genes and aberrant inflammation.Conclusions: These findings provide evidence that the downregulated levels of NLRP6 and IL18 in the colon from patients with CC may be responsible for a reduced intestinal-barrier integrity, triggering local inflammation, which in turn acts on the dysfunctional AT in obesity, increasing the expression of different inflammasome components and flaring up a vicious cycle of uncontrollable inflammatory cascades that favours a pro-tumorigenic microenvironment.Keywords: inflammasome, NLRP, inflammation, colon cancer, obesity, adipose tissue, Akkermansia muciniphila |
| format |
article |
| author |
Frühbeck G Mentxaka A Ahechu P Gómez-Ambrosi J Ramírez B Becerril S Rodríguez A Unamuno X Cienfuegos JA Casado M Burrell MA Martín M Baixauli J Valentí V Moncada R Reina G Silva C Catalán V |
| author_facet |
Frühbeck G Mentxaka A Ahechu P Gómez-Ambrosi J Ramírez B Becerril S Rodríguez A Unamuno X Cienfuegos JA Casado M Burrell MA Martín M Baixauli J Valentí V Moncada R Reina G Silva C Catalán V |
| author_sort |
Frühbeck G |
| title |
The Differential Expression of the Inflammasomes in Adipose Tissue and Colon Influences the Development of Colon Cancer in a Context of Obesity by Regulating Intestinal Inflammation |
| title_short |
The Differential Expression of the Inflammasomes in Adipose Tissue and Colon Influences the Development of Colon Cancer in a Context of Obesity by Regulating Intestinal Inflammation |
| title_full |
The Differential Expression of the Inflammasomes in Adipose Tissue and Colon Influences the Development of Colon Cancer in a Context of Obesity by Regulating Intestinal Inflammation |
| title_fullStr |
The Differential Expression of the Inflammasomes in Adipose Tissue and Colon Influences the Development of Colon Cancer in a Context of Obesity by Regulating Intestinal Inflammation |
| title_full_unstemmed |
The Differential Expression of the Inflammasomes in Adipose Tissue and Colon Influences the Development of Colon Cancer in a Context of Obesity by Regulating Intestinal Inflammation |
| title_sort |
differential expression of the inflammasomes in adipose tissue and colon influences the development of colon cancer in a context of obesity by regulating intestinal inflammation |
| publisher |
Dove Medical Press |
| publishDate |
2021 |
| url |
https://doaj.org/article/bfa5491c883747c1bb82c421c71de262 |
| work_keys_str_mv |
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oai:doaj.org-article:bfa5491c883747c1bb82c421c71de2622021-11-30T18:50:37ZThe Differential Expression of the Inflammasomes in Adipose Tissue and Colon Influences the Development of Colon Cancer in a Context of Obesity by Regulating Intestinal Inflammation1178-7031https://doaj.org/article/bfa5491c883747c1bb82c421c71de2622021-12-01T00:00:00Zhttps://www.dovepress.com/the-differential-expression-of-the-inflammasomes-in-adipose-tissue-and-peer-reviewed-fulltext-article-JIRhttps://doaj.org/toc/1178-7031Gema Frühbeck,1– 4,* Amaia Mentxaka,1,2,* Patricia Ahechu,5 Javier Gómez-Ambrosi,1– 3 Beatriz Ramírez,1– 3 Sara Becerril,1– 3 Amaia Rodríguez,1– 3 Xabier Unamuno,1,2,6 Javier A Cienfuegos,5 Marcos Casado,1 María A Burrell,7 Marina Martín,7 Jorge Baixauli,5 Victor Valentí,5 Rafael Moncada,8 Gabriel Reina,9 Camilo Silva,4 Victoria Catalán1– 3 1Metabolic Research Laboratory, Clínica Universidad de Navarra, Pamplona, Spain; 2CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Pamplona, Spain; 3Obesity and Adipobiology Group, Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain; 4Department of Endocrinology & Nutrition, Clínica Universidad de Navarra, Pamplona, Spain; 5Department of Surgery, Clínica Universidad de Navarra, Pamplona, Spain; 6Medical Engineering Laboratory, Clínica Universidad de Navarra, Pamplona, Spain; 7Department of Histology and Pathology, University of Navarra, Pamplona, Spain; 8Department of Anesthesia, Clínica Universidad de Navarra, Pamplona, Spain; 9Microbiology Laboratory, Clínica Universidad de Navarra, Pamplona, Spain*These authors contributed equally to this workCorrespondence: Gema FrühbeckDepartment of Endocrinology, Clínica Universidad de Navarra, Avda. Pío XII, 36, Pamplona, 31008, SpainTel +34 948 25 54 00 (ext. 4484)Email gfruhbeck@unav.esVictoria CatalánMetabolic Research Laboratory, Clínica Universidad de Navarra, Avda. Pío XII, 36, Pamplona, 31008, SpainTel +34 948 25 54 00 (ext. 5133)Email vcatalan@unav.esBackground: Inflammasomes maintain tissue homeostasis and their altered regulation in the colon, and the adipose tissue (AT) leads to chronic activation of inflammatory pathways promoting colon cancer (CC) development. We aimed to analyze the potential involvement of inflammasomes in obesity-associated CC.Methods: Ninety-nine volunteers [61 with obesity (OB) and 38 normoponderal (NP)] further subclassified according to the approved protocol for the diagnosis of CC (58 without CC and 41 with CC) were included in the case–control study.Results: CC (P< 0.01) and obesity (P< 0.01) were accompanied by increased mRNA levels of NLRP3, NLRP6, ASC, IL1B and NOD2 in VAT. Contrarily, patients with CC exhibited a downregulation of NLRP6 and IL18 in their colon. Additionally, we revealed that the decreased Nlrp1 (P< 0.05), Nlrp3 (P< 0.01) and Nlrp6 (P< 0.01) mRNA levels in the colon from obese rats significantly increase (P< 0.05) after caloric restriction. Adipocyte-conditioned media obtained from subjects with obesity reduced (P< 0.01) the mRNA of NLRP3 as well as molecules involved in maintaining the intestinal integrity (MUC2, CLDN1 and TJP1) and the anti-inflammatory factors FGF21, KLF4, and IL33 and in HT-29 cells. We also found that the knockdown of NLRP6 in HT-29 cells significantly upregulated (P< 0.05) the mRNA of NLRP1 and NLRP3 and inhibited (P< 0.05) the expression levels of MUC2. Finally, we showed that the incubation of HT-29 with Akkermansia muciniphila influence (P< 0.05) the inflammasome expression profile as well as intestinal integrity-related genes and aberrant inflammation.Conclusions: These findings provide evidence that the downregulated levels of NLRP6 and IL18 in the colon from patients with CC may be responsible for a reduced intestinal-barrier integrity, triggering local inflammation, which in turn acts on the dysfunctional AT in obesity, increasing the expression of different inflammasome components and flaring up a vicious cycle of uncontrollable inflammatory cascades that favours a pro-tumorigenic microenvironment.Keywords: inflammasome, NLRP, inflammation, colon cancer, obesity, adipose tissue, Akkermansia muciniphilaFrühbeck GMentxaka AAhechu PGómez-Ambrosi JRamírez BBecerril SRodríguez AUnamuno XCienfuegos JACasado MBurrell MAMartín MBaixauli JValentí VMoncada RReina GSilva CCatalán VDove Medical Pressarticleinflammasomenlrpinflammationcolon cancerobesityadipose tissueakkermansia muciniphilaPathologyRB1-214Therapeutics. PharmacologyRM1-950ENJournal of Inflammation Research, Vol Volume 14, Pp 6431-6446 (2021) |