RESUMEN
Introduction: Macrofungi, such as edible mushrooms, have been used as a valuable medical resource for millennia as a result of their antibacterial and immuno-modulatory components. Mushrooms contain dietary fibers known as ß-glucans, a class of polysaccharides previously linked to the induction of Trained Immunity. However, little is known about the ability of mushroom-derived ß-glucans to induce Trained Immunity. Methods & results: Using various powdered forms of the white button mushroom (Agaricus bisporus), we found that mouse macrophages pre-treated with whole mushroom powder (WMP) displayed enhanced responses to restimulation with TLR ligands, being particularly sensitive to Toll-like receptor (TLR)-2 stimulation using synthetic lipopeptides. This trained response was modest compared to training observed with yeast-derived ß-glucans and correlated with the amount of available ß-glucans in the WMP. Enriching for ß-glucans content using either a simulated in-vitro digestion or chemical fractionation retained and boosted the trained response with WMP, respectively. Importantly, both WMP and digested-WMP preparations retained ß-glucans as identified by nuclear magnetic resonance analysis and both displayed the capacity to train human monocytes and enhanced responses to restimulation. To determine if dietary incorporation of mushroom products can lead to Trained Immunity in myeloid cells in vivo, mice were given a regimen of WMP by oral gavage prior to sacrifice. Flow cytometric analysis of bone-marrow progenitors indicated alterations in hematopoietic stem and progenitor cells population dynamics, with shift toward myeloid-committed multi-potent progenitor cells. Mature bone marrow-derived macrophages derived from these mice displayed enhanced responses to restimulation, again particularly sensitive to TLR2. Discussion: Taken together, these data demonstrate that ß-glucans from common macrofungi can train innate immune cells and could point to novel ways of delivering bio-available ß-glucans for education of the innate immune system.
RESUMEN
SCOPE: Mushrooms are valued as an edible and medical resource for millennia. As macrofungi, they possess conserved molecular components recognized by innate immune cells like macrophages, yet unlike pathogenic fungi, they do not trigger the immune system in the same way. That these well-tolerated foods both avoid immuno-surveillance and have positive health benefits, highlights the dearth of information on the interactions of mushroom-derived products with the immune system. METHODS AND RESULTS: Using powders produced from the common white button mushroom, Agaricus bisporus, it is observed that pre-treatment of mouse and human macrophages with mushroom powders attenuates innate immune signaling triggered by microbial ligands like LPS and ß-glucans, including NFκB activation and pro-inflammatory cytokine production. This effect of mushroom powders is observed at lower doses of TLR ligands, suggesting a model of competitive inhibition whereby mushroom compounds bind and occupy innate immune receptors, precluding activation by microbial stimuli. This effect is preserved following simulated digestion of the powders. Moreover, in vivo delivery of mushroom powders attenuates the development of colitis in a DSS-mouse model. CONCLUSION: This data highlights an important anti-inflammatory role for powdered A. bisporus mushrooms, which can be further utilized to develop complementary approaches to modulate chronic inflammation and disease.