A Mangifera indica L. extract functions as a broad TLR2/4/6 signalling rheostat to attenuate MyD88/NF-κB-driven inflammation and macrophage polarization

Current therapies for immune-mediated diseases often lack precision, causing broad immunosuppression. While Mangifera indica L. extract (here referred as MIE) shows promise in resolving pain and modulating adaptive immunity, its direct impact on monocyte recruitment and macrophage polarization, remains elusive. Using a reverse translational approach, we examined the effects of MIE on primary human monocytes and macrophages from healthy donors and inflammatory bowel disease (IBD) patients. We assessed its ability to inhibit monocyte transmigration across TNF-α-activated endothelial monolayers and to modulate macrophage polarization along the M1/M2 phenotypes. Transcriptomic profiling via RNA-seq revealed several MIE-responsive pathways in human macrophages, which were subsequently validated functionally using murine peritoneal macrophages stimulated with a panel of distinct toll-like receptors (TLRs) agonists. MIE markedly impaired monocyte adhesion and transmigration across activated endothelium. In human macrophages, it selectively attenuated the pro-inflammatory M1 phenotype, robustly suppressing TNF-α secretion from both healthy donors and IBD patients, while exerting minimal effects on the M2 profile. Transcriptomic analysis revealed that MIE disrupts key inflammatory signalling networks, notably those governed by NF-κB and TLRs. Mechanistically, MIE did not exert broad TLR inhibition but instead acted as a precise immunological rheostat, dampening responses to murine TLR2, TLR4, and TLR6 agonists. TLR4-targeted modulation was mediated via downregulation of MyD88 and NF-κB expression, culminating in reduced pro-inflammatory cytokine production. We delineate a novel mechanism for MIE as a selective rheostat of the TLR2/4/6 axis for restoring innate immune homeostasis in inflammatory-based diseases. • Mangifera indica L. extract (MIE) blocks monocyte recruitment and selectively inhibits pro-inflammatory M1 macrophages, sparing M2 activity. • MIE acts as a precise TLR rheostat, specifically targeting pro-inflammatory TLR2/4/6 pathways to avoid broad immunosuppression. • MIE modulates the MyD88/NF-κB axis, preventing this key factor's nuclear translocation and cytokine production after TLR4 activation. • This multi-level strategy recalibrates innate immunity, offering a targeted therapeutic for chronic inflammatory disease.