MANGANESE (II) MODULATES MACROPHAGES IMMUNE RESPONSE TO LIPOPOLYSACCHARIDE

Background: Manganese (Mn) impact on human health is often studied regarding its neurotoxicity, leading to a Parkinson-like pathology termed manganism. Since scientific reports indicate manganese neurotoxicity as potentially inflammation-driven, our study aims to investigate the influence of acute and chronic manganese (II) chloride (MnCl2) exposure on macrophages ability to react to an inflammatory stimulus. Methods: The experimental model consisted in in vitro treatment of RAW264.7 murine macrophage-like cells with MnCl2 for two different time intervals in an attempt to simulate acute intoxication and chronic intoxication. Non-cytotoxic MnCl2 concentration values were determined using MTT assay. Acute and chronic exposure to manganese was followed by lipopolysaccharide (LPS) stimulation. Relevant pro-inflammatory cytokine secretion, mRNA transcripts and NF-κB p65 nuclear translocation were measured. Results: LPS stimulation of cells treated with non-cytotoxic MnCl2 levels triggered enhanced TNF-α (Tumor Necrosis Factor α) secretion in the investigated acute model, whereas in the chronic exposure model only an intermediate MnCl2 concentration (37.5 μM) caused a rise in cytokine secretion. Acute treatment induced a dosedependent upregulation of Tnfα and Nos2 (Nitric oxide synthase 2) gene transcription coupled with an increasing trend in nuclear distribution of p65 subunit of NF-κB complex. Chronic treatment induced a dose-dependent downregulation of pro-inflammatory genes alongside an increase in Ho1 (Heme oxygenase 1) transcription. Conclusions: Our results suggest that manganese (II) has the potential to modulate macrophage inflammatory response development. Acute exposure generally intensifies inflammatory processes, while chronic exposure induces an attenuation of these, possibly due to heme oxygenase-1 inhibition of NF-kB signaling. Keywords: Manganese, Inflammation, Lipopolysaccharide, Cytokines, Heme oxygenase 1