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Effect of haptoglobin (purified from human serum) on gene expression in monocyte-derived macrophages.

ABSTRACT: Haptoglobin is a major serum protein that sequesters free hemoglobin. Moreover, haptoglobin regulates the inflammatory response in the absence of hemoglobin. Conflicting functional outcomes are reported, whereas involvement of NFκB is suggested consistently. Our data indicate that purified haptoglobin induces NFκB-dependent transcription through toll-like receptor 4. Notably, haptoglobin itself is dispensable for this effect. We show here that haptoglobin binds lipopolysaccharides from different bacterial species with micromolar affinities. This finding explains previous divergent observations. Pro-inflammatory responses elicited by purified haptoglobin are caused by heterogeneous lipopolysaccharides associated with the protein. Given its abundance in human serum, haptoglobin constitutes a buffer for serum-borne lipopolysaccharide. Restricted lipopolysaccharide availability dampens inflammatory responses. Concordantly, NFκB activation in primary macrophages is delayed relative to stimulation with pure lipopolysaccharide. Our findings warrant evaluation of therapeutic benefits of haptoglobin for non-hemolytic conditions as well as re-evaluation of purification strategies and will furthermore allow to disentangle mechanisms of haptoglobin-dependent immunoregulation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE215916 | GEO | 2022/10/24

REPOSITORIES: GEO

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Project description:Trypanosoma brucei requires haemoglobin for survival in the mammalian bloodstream. Haptoglobin (Hp), a host protein known to bind haemoglobin, was determined as a key component for haemoglobin acquisition by the parasite. Here, we investigated the impact of haptoglobin deficiency on T. brucei brucei infection and the parasite´s capacity to internalise haemoglobin in the Hp-/- mouse model. The infected Hp-/- mice exhibited normal disease progression, with minimal weight loss and no apparent organ pathology similarly to control mice. While the proteomic profile of mouse sera significantly changed in response to T. b. brucei, no differences in the infection response markers of blood plasma have been observed between Hp-/- and control Black mice. Similarly, very few quantitative differences have been observed between the proteomes of parasites harvested from Hp-/- and Black mice, entailing both endogenous proteins and internalised host proteins. While haptoglobin was indeed absent from parasites isolated from Hp-/-mice, haemoglobin peptides were unexpectedly detected in parasites from both Hp-/- and Black mice. This was verified by western blotting, EM immunolabeling of parasites cryosections, and analytical quantification of haem cofactors in the parasites extracts. Combined, the data support the Hp dispensability for haemoglobin internalisation by T. b. brucei during infection in mice. To further explore this phenomenon, we have generated T. b. brucei haptoglobin-haemoglobin receptor (HpHbR) knock-outs and used them to infect Hp-/- and control mice. The HpHbR-knock-out trypanosomes internalised significantly less haemoglobin from Hp-/- mice compared to those isolated from Black mice strongly suggesting that T. b. brucei employs an HpHbR-independent Hp-mediated mode for haemoglobin internalisation. Our study reveals a so-far hidden flexibility of haemoglobin acquisition by T. b. brucei and offers novel insights into alternative haemoglobin uptake pathways.

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Effect of haptoglobin (purified from human serum) on gene expression in monocyte-derived macrophages.

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