Chitin Derived Small Molecule AVR-48 Reprograms the Resting Macrophages to an Intermediate Phenotype and Decrease Pseudomonas aeruginosa Mouse Lung Infection

Abstract

AVR-48 is a structural derivative of chitin previously shown by our laboratory to significantly decrease lung injury parameters in LPS, hyperoxia and sepsis-induced rodent models. The current study objectives are to determine the cellular mechanism of action and demonstrate efficacy in a mouse bacterial lung infection model. For in vitro receptor binding and macrophage polarization studies, C57Bl/6J mouse derived spleens and human peripheral blood mononuclear cells (hPBMCs) were treated with AVR-48 ± LPS or biotin conjugated AVR-48. Different macrophage types were determined using flow cytometry and secreted cytokines were measured using ELISA. In vivo, a CD-1 mouse Pseudomonas aeruginosa lung infection was treated with AVR-48, assessing bacterial colony forming unit (CFU), IL-10 and IL-17A levels in lung and blood samples. AVR-48 binds to both the toll-like receptor 4 (TLR4) and the CD163 receptor on mouse monocytes. In hPBMCs, frequency of intermediate macrophages increased upon AVR-48 treatment for 72 h. Increased bacterial phagocytosis/intracellular killing were observed in THP-1 cells and reduction in CFU in CD-1 mouse lungs. Binding of AVR-48 to both TLR4 and CD163 receptors bring the macrophages to an intermediary stage, resulting in increased phagocytosis and decreased inflammation, altogether providing an optimal immune balance for treating lung injury and infection.

The Immune Modulating Potential of Supplementing Cobb500 Broiler Chickens With Cricket and Shrimp Chitin and Chitosan

“…Research has indicated that chitosan (CHS), a (1-4)-linked d-glucosamine, and chitin (CHT), a (1-4)-N-acetyl-d-glucosamine, can enhance the immune responses of broiler chickens (Menconi et al, 2014). There have been findings that CHT enhances macrophage activation and the production of inflammatory cytokines (Behera et al, 2022;Komi et al, 2018). Additional investigations found that CHS increased the nitric oxide (NO) manufacturing process, activated macrophages, increased iNOS expression and activity, and secreted more TNF, IL-1, and IL-2 in broiler chicks (Li et al, 2014).…”