Blocking Dectin-1 prevents colorectal tumorigenesis by suppressing prostaglandin E2 production in myeloid-derived suppressor cells and enhancing IL-22 binding protein expression

Abstract

Dectin-1 (gene Clec7a), a receptor for β-glucans, plays important roles in the host defense against fungi and immune homeostasis of the intestine. Although this molecule is also suggested to be involved in the regulation of tumorigenesis, the role in intestinal tumor development remains to be elucidated. In this study, we find that azoxymethane-dextran-sodium-sulfate-induced and ApcMin-induced intestinal tumorigenesis are suppressed in Clec7a−/− mice independently from commensal microbiota. Dectin-1 is preferentially expressed on myeloid-derived suppressor cells (MDSCs). In the Clec7a−/− mouse colon, the proportion of MDSCs and MDSC-derived prostaglandin E2 (PGE2) levels are reduced, while the expression of IL-22 binding protein (IL-22BP; gene Il22ra2) is upregulated. Dectin-1 signaling induces PGE2-synthesizing enzymes and PGE2 suppresses Il22ra2 expression in vitro and in vivo. Administration of short chain β-glucan laminarin, an antagonist of Dectin-1, suppresses the development of mouse colorectal tumors. Furthermore, in patients with colorectal cancer (CRC), the expression of CLEC7A is also observed in MDSCs and correlated with the death rate and tumor severity. Dectin-1 signaling upregulates PGE2-synthesizing enzyme expression and PGE2 suppresses IL22RA2 expression in human CRC-infiltrating cells. These observations indicate a role of the Dectin-1-PGE2-IL-22BP axis in regulating intestinal tumorigenesis, suggesting Dectin-1 as a potential target for CRC therapy.

The antidepressive mechanism of Longya Lilium combined with Fluoxetine in mice with depression-like behaviors

“…Therefore, it is hypothesized that Dragon Tooth Lily and Fluoxetine may affect depression through the COX-2/PGE2 pathway. In addition, IL-22 is an essential inflammatory factor regulated by PGE2 in immune cells 39 , and PGE2 promotes IL-22 production in T cells, thereby contributing to the development of allergic contact dermatitis 40 . Moreover, levels of IL-22 are positively associated with depression, and inhibiting IL-22 expression improves depressive behavior in mice models of colorectal cancer comorbid with depression 41 , 42 .…”

“…Hence, we hypothesize that Longya Lily and fluoxetine may exert their effects through the COX-2/PGE2 pathway in depression. In addition, IL22 is a pivotal inflammatory factor regulated by PGE2 in immune cells 39 . Therefore, we selected the PGE2/IL22 axis as the downstream signaling pathway for this study.…”

Know your neighbors: microbial recognition at the intestinal barrier and its implications for gut homeostasis and inflammatory bowel disease

“…Several innate immune receptors and the resulting crosstalk between the drivers of these signaling cascades have so far only been characterized in myeloid cells, and their independent roles on IECs warrants further investigation. However, in the above-mentioned study, Tang et al could not specifically determine the effect of Dectin-1 receptor ablation on PGE2, as well as Il22ra2 expression in the intestinal epithelial cells (Tang et al, 2023).…”

“…Recently, the β-glucan receptor Dectin-1 has been shown to be a positive inducer of intestinal prostaglandin E2 (PGE2) secretion by myeloid-derived suppressor cells (MDSCs), leading to enhanced colorectal tumorigenesis in human colorectal cancer patient cohorts as well as in AOM-DSS and Apc Min/+ mouse models. Dectin-1 signaling was correlated with increased PGE2synthase expression and suppressed IL22RA2 in human CRCinfiltrating cells (Tang et al, 2023). The intestinal epithelial barrier is the primary site of CRC disease pathogenesis and progression, and thus it is intriguing to question the exact role of Dectin-1 signaling, among other innate immune signaling in IECs in CRC development and pathogenesis.…”

The role of fungi in the diagnosis of colorectal cancer

“…More interestingly, recent observations indicate the involvement of the Dectin-1-PGE2-IL-22BP axis in regulating intestinal tumorigenesis. Dectin-1, encoded by the Clec7a gene, is known to play important roles in host defence against fungi and immune homoeostasis in the intestine and will likely be a therapeutic target in the future (Tang et al 2023 ). Therefore, the assessment of fungal-related biomarkers may also help identify risk factors for CRC in combination with other non-invasive examination methods (Pratt et al 2022 ).…”