Immunomodulatory Potential of Erica multiflora Secondary Metabolites: Insights into Plant–Mammal Interactions and Anti-Inflammatory Mechanisms

Background:
Plants synthesize a wide variety of secondary metabolites that support ecological defense and communication, many of which also exert biological activity in mammals. Erica multiflora, a Mediterranean species with a rich phenolic composition, remains underexplored for its immunomodulatory properties. This study aimed to evaluate the capacity of Erica multiflora hydromethanolic extract to modulate macrophage phenotype and inflammatory responses, thereby providing insight into the role of plant-derived metabolites in immune regulation

Methods:
Murine bone marrow–derived macrophages (BMDMs) were treated with increasing concentrations of extract (12.5–100 µg/mL) to assess dose-dependent effects. Cytotoxicity was evaluated using the lactate dehydrogenase (LDH) assay. Flow cytometry was performed to quantify macrophage polarization markers: CD86, CC chemokine receptor 2 (CCR2), and major histocompatibility complex class II (MHC-II) for pro-inflammatory (M1) macrophages, and CD206 for anti-inflammatory (M2) macrophages. Tumor necrosis factor-alpha (TNF-α) release following lipopolysaccharide (LPS) stimulation was quantified using enzyme-linked immunosorbent assay (ELISA).

Results:
The extract demonstrated low cytotoxicity (>90% viability at all tested concentrations). TNF-α secretion decreased by approximately 45–60% relative to the LPS-stimulated control. Flow cytometry showed a 25–40% reduction in M1-associated markers (CD86, CCR2, MHC-II) and a 30–50% increase in the M2 marker CD206, indicating a phenotypic shift toward an anti-inflammatory state.

Conclusion:
Erica multiflora metabolites exhibit strong immunomodulatory potential by reducing inflammatory cytokine release and promoting anti-inflammatory macrophage polarization. These findings highlight the relevance of plant secondary metabolites as natural modulators of innate immunity and support their potential therapeutic value in inflammation-associated diseases.