New Insights into the Pivotal Role of Iron/Heme Metabolism in TLR4/NF-κB Signaling-Mediated Inflammatory Responses in Human Monocytes.

Dong Young Kang,Nipin Sp,Kyoung-Jin Jang,Jin-Moo Lee,Eun Seong Jo

doi:10.3390/cells10102549

Abstract

Iron metabolism and heme biosynthesis are essential processes in cells during the energy cycle. Alteration in these processes could create an inflammatory condition, which results in tumorigenesis. Studies are conducted on the exact role of iron/heme metabolism in induced inflammatory conditions. This study used lipopolysaccharide (LPS)- or high-glucose-induced inflammation conditions in THP-1 cells to study how iron/heme metabolism participates in inflammatory responses. Here, we used iron and heme assays for measuring total iron and heme. We also used flow cytometry and Western blotting to analyze molecular responses. Our results demonstrated that adding LPS or high-glucose induced iron formation and heme synthesis and elevated the expression levels of proteins responsible for iron metabolism and heme synthesis. We then found that further addition of heme or 5-aminolevulinic acid (ALA) increased heme biosynthesis and promoted inflammatory responses by upregulating TLR4/NF-κB and inflammatory cytokine expressions. We also demonstrated the inhibition of heme synthesis using succinylacetone (SA). Moreover, N-MMP inhibited LPS- or high-glucose-induced inflammatory responses by inhibiting TLR4/NF-κB signaling. Hence, iron/heme metabolism checkpoints could be considered a target for treating inflammatory conditions.

Highlights

Inflammatory responses occur because of inflammation caused by foreign substances, such as chemicals, bacteria, heat, or toxins
The results showed suppression in Fe2+, indicating an increase in iron transport as Fe2+ was converted to ferric ion (Fe3+ ) so that an increased amount of total iron is converted for iron metabolism (Figure 1C)
High glucose in THP-1 cells suggested the conversion of Fe2+ to Fe3+ for iron metabolism and elevation in expression levels of divalent metal transporter 1 (DMT1) (Figure 1D)

Summary

Introduction

Inflammatory responses occur because of inflammation caused by foreign substances, such as chemicals, bacteria, heat, or toxins. Inflammatory responses begin by cell surface receptor signaling, where toll-like receptors (TLRs) that are considered key receptor molecules recognize harmful stimuli and send signals to activate inflammatory pathways. These pathways aid in releasing proinflammatory cytokines to recruit inflammatory cells for inflammatory responses [3,4]. Among TLRs, TLR2 and TLR4 play a vital role in the inflammatory response by activating molecular signaling [5]. These TLRs promote signals to the cytoplasm, where many molecules receive the signal and respond. Nuclear factor-kappa B (NF-κB), which is activated, mediates inflammatory and immune responses through the canonical or noncanonical

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