Obesity exacerbates colitis-associated cancer via IL-6-regulated macrophage polarisation and CCL-20/CCR-6-mediated lymphocyte recruitment

Claudia M Wunderlich; P Justus Ackermann; Anna Lena Ostermann; Petra Adams-Quack; Merly C Vogt; My-Ly Tran; Alexei Nikolajev; Ari Waisman; Christoph Garbers; Sebastian Theurich; Jan Mauer; Nadine Hövelmeyer; F Thomas Wunderlich

doi:10.1038/s41467-018-03773-0

Obesity exacerbates colitis-associated cancer via IL-6-regulated macrophage polarisation and CCL-20/CCR-6-mediated lymphocyte recruitment

Nat Commun. 2018 Apr 25;9(1):1646. doi: 10.1038/s41467-018-03773-0.

Affiliations

¹ Max Planck Institute for Metabolism Research Cologne, Institute for Genetics, University of Cologne, Cologne Excellence Cluster on Cellular Stress Responses in Aging-associated Diseases (CECAD), Center for Molecular Medicine Cologne (CMMC), Center for Endocrinology, Diabetes and Preventive Medicine (CEDP) Cologne, 50931, Cologne, Germany.
² Institute for Molecular Medicine, University Hospital Mainz, 55131, Mainz, Germany.
³ Department of Biochemistry, Kiel University, Medical Faculty, 24118, Kiel, Germany.
⁴ Department of Pharmacology, Weill Cornell Medical College, Cornell University, New York, NY, 10065, USA.
⁵ Max Planck Institute for Metabolism Research Cologne, Institute for Genetics, University of Cologne, Cologne Excellence Cluster on Cellular Stress Responses in Aging-associated Diseases (CECAD), Center for Molecular Medicine Cologne (CMMC), Center for Endocrinology, Diabetes and Preventive Medicine (CEDP) Cologne, 50931, Cologne, Germany. [email protected].

Abstract

Colorectal cancer (CRC) is one of the most lethal cancers worldwide in which the vast majority of cases exhibit little genetic risk but are associated with a sedentary lifestyle and obesity. Although the mechanisms underlying CRC and colitis-associated colorectal cancer (CAC) remain unclear, we hypothesised that obesity-induced inflammation predisposes to CAC development. Here, we show that diet-induced obesity accelerates chemically-induced CAC in mice via increased inflammation and immune cell recruitment. Obesity-induced interleukin-6 (IL-6) shifts macrophage polarisation towards tumour-promoting macrophages that produce the chemokine CC-chemokine-ligand-20 (CCL-20) in the CAC microenvironment. CCL-20 promotes CAC progression by recruiting CC-chemokine-receptor-6 (CCR-6)-expressing B cells and γδ T cells via chemotaxis. Compromised cell recruitment as well as inhibition of B and γδ T cells protects against CAC progression. Collectively, our data reveal a function for IL-6 in the CAC microenvironment via lymphocyte recruitment through the CCL-20/CCR-6 axis, thereby implicating a potential therapeutic intervention for human patients.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Transformation, Neoplastic / immunology
Cell Transformation, Neoplastic / pathology
Chemokine CCL20 / immunology
Chemokine CCL20 / metabolism*
Chemotaxis / immunology
Colitis, Ulcerative / chemically induced
Colitis, Ulcerative / immunology
Colitis, Ulcerative / pathology*
Colon / drug effects
Colon / immunology
Colon / pathology
Colorectal Neoplasms / immunology*
Colorectal Neoplasms / pathology
Diet, High-Fat / adverse effects
Disease Models, Animal
Disease Progression
Female
Humans
Interleukin-6 / metabolism*
Interleukin-6 Receptor alpha Subunit / genetics
Interleukin-6 Receptor alpha Subunit / metabolism
Intestinal Mucosa / drug effects
Intestinal Mucosa / immunology
Intestinal Mucosa / pathology
Lymphocytes / immunology
Lymphocytes / metabolism
Macrophages / immunology
Macrophages / metabolism
Mice
Mice, Knockout
Obesity / etiology
Obesity / immunology*
Receptors, CCR6 / genetics
Receptors, CCR6 / metabolism*
Signal Transduction / immunology
Tumor Microenvironment / immunology

Substances

CCL20 protein, mouse
CCR6 protein, mouse
Chemokine CCL20
Interleukin-6
Interleukin-6 Receptor alpha Subunit
Receptors, CCR6
interleukin-6, mouse