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 to 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.

Citation

Schettino A, Saviano A, Marigliano N, Smimmo M, Esposito E, Begum J, Fatima A, Urbanowski AM, Mahony C, Khormi AM, Mansour AA, Iqbal TH, McGettrick HM, Iqbal AJ, Maione F. A Mangifera indica L. extract functions as a broad TLR2/4/6 signalling rheostat to attenuate MyD88/NF-κB-driven inflammation and macrophage polarization. Pharmacol Res. 2026 Jan 14;224:108099. doi: 10.1016/j.phrs.2026.108099. Epub ahead of print.

Type

Article