title: CCR1 antagonism attenuates T cell trafficking to omentum and liver in obesity-associated cancer.
abstract: Obesity is a global health problem presenting serious risk of disease fuelled by chronic inflammation, including type 2 diabetes mellitus, cardiovascular disease, liver disease and cancer. Visceral fat, in particular the omentum and liver of obese individuals are sites of excessive inflammation. We propose that chemokine-mediated trafficking of pro-inflammatory cells to the omentum and liver contributes to local and subsequent systemic inflammation. Oesophagogastric adenocarcinoma (OAC) is an exemplar model of obesity and inflammation driven cancer. We have demonstrated that T cells actively migrate to the secreted factors from the omentum and liver of OAC patients and that both CD4(+) and CD8(+) T cells bearing the chemokine receptor CCR5 are significantly more prevalent in these tissues compared to matched blood. The CCR5 ligand and inflammatory chemokine MIP-1α is also secreted at significantly higher concentrations in the omentum and liver of our OAC patient cohort compared to matched serum. Furthermore, we report that MIP-1α receptor antagonism can significantly reduce T cell migration to the secreted factors from OAC omentum and liver. These novel data suggest that chemokine receptor antagonism may have therapeutic potential to reduce inflammatory T cell infiltration to the omentum and liver and in doing so, may ameliorate pathological inflammation in obesity and obesity-associated cancer.
authors.affiliation: Department of Surgery, Trinity College Dublin, Dublin, Ireland.
authors.forename: Melissa J
authors.initials: MJ
authors.lastname: Conroy
authors.affiliation: Department of Surgery, Trinity College Dublin, Dublin, Ireland.
authors.forename: Karen C
authors.initials: KC
authors.lastname: Galvin
authors.affiliation: Department of Surgery, Trinity College Dublin, Dublin, Ireland.
authors.forename: Maria E
authors.initials: ME
authors.lastname: Kavanagh
authors.affiliation: Department of Surgery, Trinity College Dublin, Dublin, Ireland.
authors.forename: Ann Marie
authors.initials: AM
authors.lastname: Mongan
authors.affiliation: Department of Surgery, Trinity College Dublin, Dublin, Ireland.
authors.forename: Suzanne L
authors.initials: SL
authors.lastname: Doyle
authors.affiliation: National Oesophageal and Gastric Centre, St James's Hospital, Dublin, Ireland.
authors.forename: Niamh
authors.initials: N
authors.lastname: Gilmartin
authors.affiliation: School of Biochemistry and Immunology, Trinity College Dublin, Dublin, Ireland.
authors.forename: Cliona
authors.initials: C
authors.lastname: O'Farrelly
authors.affiliation: Department of Surgery, Trinity College Dublin, Dublin, Ireland.|National Oesophageal and Gastric Centre, St James's Hospital, Dublin, Ireland.
authors.forename: John V
authors.initials: JV
authors.lastname: Reynolds
authors.affiliation: Department of Surgery, Trinity College Dublin, Dublin, Ireland.
authors.forename: Joanne
authors.initials: J
authors.lastname: Lysaght
mesh_terms: D000273:Adipose Tissue / Q000473:pathology; D000368:Aged; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D016022:Case-Control Studies; D002465:Cell Movement / Q000276:immunology*; D018925:Chemokines / Q000378:metabolism; D017077:Culture Media, Conditioned / Q000494:pharmacology; D005260:Female; D006801:Humans; D008099:Liver / Q000473:pathology*; D008297:Male; D009369:Neoplasms / Q000097:blood / Q000209:etiology / Q000276:immunology*; D009765:Obesity / Q000150:complications*; D009852:Omentum / Q000473:pathology*; D054389:Receptors, CCR1 / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D018925:Chemokines; D017077:Culture Media, Conditioned; D054389:Receptors, CCR1