Heme Interferes With Complement Factor I-Dependent Regulation by Enhancing Alternative Pathway Activation

Heme Interferes With Complement Factor I-Dependent Regulation by Enhancing Alternative Pathway Activation

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Hemolysis, as a result of disease or exposure to biomaterials, is characterized by excess amounts of cell-free heme intravascularly and consumption of the protective heme-scavenger proteins in plasma.The liberation of heme has been linked to the ORG CURCUMIN + BIO PERIN activation of inflammatory systems, including the complement system, through alternative pathway activation.Here, we investigated the impact of heme on the regulatory function of the complement system.

Heme dose-dependently inhibited factor I-mediated degradation of soluble and surface-bound C3b, when incubated in plasma or buffer with complement regulatory proteins.Inhibition occurred with factor H and soluble complement receptor 1 as co-factors, and the mechanism was linked to the direct heme-interaction with factor I.The heme-scavenger protein hemopexin was the main contaminant in purified factor I preparations.

This led us to identify that hemopexin formed a complex with factor I in normal human plasma.These complexes were significantly reduced during acute vasoocclusive pain crisis in patients with sickle cell disease, but the complexes were normalized at their baseline outpatient clinic visit.Hemopexin exposed a protective function of factor I activity in vitro, but only when it was present before the addition of heme.

In conclusion, Leveler we present a mechanistic explanation of how heme promotes uncontrolled complement alternative pathway amplification by interfering with the regulatory capacity of factor I.Reduced levels of hemopexin and hemopexin-factor I complexes during an acute hemolytic crisis is a risk factor for heme-mediated factor I inhibition.