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

• DOI: 10.1038/s41467-018-03773-0
• Publication Date: 2018-04-19T09:35:04Z
• Authors: Claudia M. Wunder...; 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
• Keywords: 0301 basic medicine; Colon; Science; Diet, High-Fat; Article; Mice; 03 medical and health sciences; 616; Animals; Humans; Lymphocytes; Obesity; Intestinal Mucosa; Mice, Knockout; 2. Zero hunger; Chemokine CCL20; Interleukin-6; Chemotaxis; Macrophages; Q; ddc:no; 3. Good health; Disease Models, Animal; Cell Transformation, Neoplastic; Interleukin-6 Receptor alpha Subunit; Disease Progression; Colitis, Ulcerative; Female; Colorectal Neoplasms

AbstractColorectal 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.