Haptoglobin buffers lipopolysaccharides to safeguard against aberrant NFκB activation

It has remained yet unclear which soluble factors regulate the anti-inflammatory macrophage phenotype observed in both homeostasis and tumourigenesis. We show here that haptoglobin, a major serum pro-tein with elusive immunoregulatory properties, binds and buffers serum-borne bacterial lipopolysaccharides to attenuate activation of NF{kappa}B in macrophages. Haptoglobin binds different lipopolysaccharides with low micromolar affinities. Given its abundance, haptoglobin constitutes a buffer for lipopolysaccharides, shielding them to safeguard against aberrant inflammatory reactions caused by small fluctuations. Concordantly, NF{kappa}B activation by haptoglobin-associated lipopolysaccharides 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 elucidate mechanisms of enhanced immunosuppression by oncofetal haptoglobin.