LGR6 frameshift variant abrogates receptor expression on select leukocyte subsets and associates with viral infections.

The leucine-rich repeat-containing G-protein-coupled receptor 6 (LGR6) was recently identified as the cognate receptor for the pro-resolving mediator Maresin (MaR)1. To address the biological role of LGR6 in humans, we investigated the functional impact of a genetic variant in the gene encoding for LGR6, which is predicted to lead to a frameshift mutation in one of the receptor isoforms, on both receptor expression and immune cell responses. In neutrophils, monocytes, and NK cells from volunteers homozygous for this variant, we found a significant downregulation in the expression of LGR6 when compared with controls without the variant. Whereas LGR6 expression was essentially similar in monocyte-derived macrophages and CD8+ T-cells. Functionally loss of LGR6 expression was linked with a decreased ability of neutrophils and monocytes to phagocytose bacteria. We observed an increase in neutrophil chemotaxis and leukotriene B4 (LTB4) production, and increased expression of activation markers, including markers for platelet-leukocyte phagocyte heterotypic aggregates, such as CD41, in neutrophils and monocytes from the variant group. Using data from the UK Biobank we found that at a population level the rs4266947 variant which is in high linkage disequilibrium with rs74355478 was associated with a higher incidence of viral infections. Intriguingly, neutrophils, NK cells and CD8+ T-cells from volunteers with the LGR6 variant displayed altered viral responses when stimulated with Toll-like receptor (TLR)3, TLR7/TLR8 and TLR9 agonists. Together these findings shed new light on the cell type-specific regulation of LGR6 expression and the role of this receptor in directing host immune responses.

Pro-tumorigenic role of type 2 diabetes-induced cellular senescence in colorectal cancer.

Colorectal cancer (CRC) is the second leading cause of cancer-related mortality worldwide. The disease still remains incurable and highly lethal in the advanced stage, representing a global health concern. Therefore, it is essential to understand the causes and risk factors leading to its development. Because age-related cellular senescence and type 2 diabetes (T2D) have been recognised as risk factors for CRC development, the recent finding that type 2 diabetic patients present an elevated circulating volume of senescent cells raises the question whether type 2 diabetes facilitates the process of CRC tumorigenesis by inducing premature cell senescence. In this review, we will discuss the mechanisms according to which T2D induces cellular senescence and the role of type 2 diabetes-induced cellular senescence in the pathogenesis and progression of colorectal cancer. Lastly, we will explore the current therapeutic approaches and challenges in targeting senescence.