An investigation into the pro-inflammatory properties of heme in primary human macrophages

Abstract

Evidence suggests that haem may represent a novel DAMP. Haem generated by intra and extra-vascular haemolysis activates innate immune cells and non-hematopoietic cells, promoting pro-inflammatory activities, such as leukocyte activation, migration and infiltration, adhesion molecule activation, cytokine release and inflammasome formation. Our data suggest that haem is a potent driver of inflammatory mediator, matrix metalloprotease (MMP) and S100 protein expression in the primary human macrophages (hMACs). Here we also demonstrate that exposure of hMACs to haem induces IL-1² processing in LPS-primed hMACs in a capase-1 and NLRP3-dependent manner. We found that haem activates PI3 kinase, MEK and ERK and induces hMACs to upregulate their expressions of MMP1 and MMP9 and the damage-associated molecules, S100A8 and S100A12. We postulate that S100A8 may act as a sterile priming stimuli in intravascular hemolytic diseases and data provide new insights regarding the mechanisms by which haemoglobin and its products induce inflammatory responses. (AU)