IL-1R signaling drives enteric glia-macrophage interactions in colorectal cancer.

Enteric glia have been recently recognized as key components of the colonic tumor microenvironment indicating their potential role in colorectal cancer pathogenesis. Although enteric glia modulate immune responses in other intestinal diseases, their interaction with the colorectal cancer immune cell compartment remains unclear. Through a combination of single-cell and bulk RNA-sequencing, both in murine models and patients, here we find that enteric glia acquire an immunomodulatory phenotype by bi-directional communication with tumor-infiltrating monocytes. The latter direct a reactive enteric glial cell phenotypic and functional switch via glial IL-1R signaling. In turn, tumor glia promote monocyte differentiation towards pro-tumorigenic SPP1+ tumor-associated macrophages by IL-6 release. Enteric glia cell abundancy correlates with worse disease outcomes in preclinical models and colorectal cancer patients. Thereby, our study reveals a neuroimmune interaction between enteric glia and tumor-associated macrophages in the colorectal tumor microenvironment, providing insights into colorectal cancer pathogenesis.

Behavioral changes occur earlier than redox alterations in developing zebrafish exposed to Mancozeb.

As agriculture expands to provide food and wellbeing to the world's growing population, there is a simultaneous increasing concern about the use of agrochemicals, which can harm non-target organisms, mainly in the aquatic environment. The fungicide Mancozeb (MZ) has been used on a large-scale and is a potent inducer of oxidative stress. Therefore, there is an urgent need for the development of more sensitive biomarkers designed to earlier biomonitoring of this compound. Here we tested the hypothesis that behavioral changes induced by sublethal MZ concentrations would occur first as compared to biochemical oxidative stress markers. Embryos at 4 h post-fertilization (hpf) were exposed to Mancozeb at 5, 10 and 20 µg/L. Controls were kept in embryo water only. Behavioral and biochemical parameters were evaluated at 24, 28, 72, and 168 hpf after MZ exposure. The results showed that MZ significantly altered spontaneous movement, escape responses, swimming capacity, and exploratory behavior at all exposure times. However, changes in ROS steady-stead levels and the activity of antioxidant enzymes were observable only at 72 and 168 hpf. In conclusion, behavioral changes occurred earlier than biochemical alterations in zebrafish embryos exposed to MZ, highlighting the potential of behavioral biomarkers as sensitive tools for biomonitoring programs.