Haptoglobin buffers lipopolysaccharides to safeguard against aberrant NFκB activation

Abstract

AbstractHaptoglobin is the major detoxifier of hemoglobin. Moreover, haptoglobin modulates the inflammatory responseviaNFκB. In some studies haptoglobin represses and in others it activates NFκB. We show here that these conflicting results are explainable by haptoglobin’s ability to bind and buffer lipopolysaccharides, which are bacterial activators of innate immune responses. While haptoglobin preparations from human serum induced NFκB-dependent transcriptionviatoll-like receptor 4, haptoglobin itself was dispensable. The effect was rather caused by associated lipopolysaccharides that were apparently enriched during purification. Haptoglobin binds different lipopolysaccharides with low micromolar affinities. Given its abundance, haptoglobin constitutes a buffer for serum-borne lipopolysaccharides, shielding them to safeguard against aberrant inflammatory reactions caused by small fluctuations. Concordantly, NFκB activation by haptoglobin was delayed relative to stimulation with pure lipopolysaccharide. Our findings warrant evaluation of therapeutic benefits of haptoglobin for inflammatory conditions and re-evaluation of purification strategies. Finally, they allow to disentangle mechanisms of immunosuppression by oncofetal haptoglobin.