Editing Haptoglobin (section)

== Function ==
Hemoglobin that has been released into the blood plasma by damaged red blood cells has harmful effects. The ''HP'' gene encodes a preproprotein that is processed to yield both alpha and beta chains, which subsequently combines as a [[tetramer protein|tetramer]] to produce haptoglobin. Haptoglobin functions to bind the free plasma [[hemoglobin]], which allows [[degradative enzyme]]s to gain access to the hemoglobin while at the same time preventing loss of iron through the kidneys and protecting the kidneys from damage by hemoglobin.<ref name="entrez">{{cite web | title = Entrez Gene: HP | url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=3240 }}</ref> 

The cellular receptor target of Hp is the monocyte/macrophage scavenger receptor, [[CD163]].<ref name="Schaer Vinchi Ingoglia Tolosano p. "/> Following Hb-Hp binding to CD163, cellular internalization of the complex leads to globin and heme metabolism, which is followed by adaptive changes in antioxidant and iron metabolism pathways and macrophage phenotype polarization.<ref name="Schaer Vinchi Ingoglia Tolosano p. "/>

Hp has hemoglobin-independent immunomodulatory functions. It dampens [[lipopolysaccharide]]-induced [[cytokine]] expression.<ref>{{cite journal | vauthors = Arredouani MS, Kasran A, Vanoirbeek JA, Berger FG, Baumann H, Ceuppens JL | title = Haptoglobin dampens endotoxin-induced inflammatory effects both in vitro and in vivo | journal = Immunology | volume = 114 | issue = 2 | pages = 263–271 | date = February 2005 | pmid = 15667571 | pmc = 1782073 | doi = 10.1111/j.1365-2567.2004.02071.x }}</ref> Lipopolysaccharides directly bind to Hp, which, due to the high abundance of Hp in serum, results in their buffering and shielding from [[toll-like receptor 4]]. Functionally, this results in delayed activation of the [[NF-κB]] pathway.<ref>{{cite journal | vauthors = Zein L, Grossmann J, Swoboda H, Borgel C, Wilke B, Awe S, Nist A, Stiewe T, Stehling O, Freibert SA, Adhikary T, Chung HR | title = Haptoglobin buffers lipopolysaccharides to delay activation of NFκB | journal = Frontiers in Immunology | volume = 15 | pages = 1401527 | date = 2024 | pmid = 39416789 | pmc = 11479958 | doi = 10.3389/fimmu.2024.1401527 | doi-access = free }}</ref>


===Difference from hemopexin===

When hemoglobin is released from RBCs within the physiologic range of haptoglobin, the potential deleterious effects of hemoglobin are prevented. During hyper-hemolytic conditions or with chronic hemolysis, haptoglobin is depleted and hemoglobin readily distributes to tissues where it might be exposed to oxidative conditions. In such conditions, heme can be released from ferric (Fe<sup>3+</sup>-bound) hemoglobin. The free heme can then accelerate tissue damage by promoting peroxidative reactions and activation of inflammatory cascades. [[Hemopexin]] (Hx) is another plasma glycoprotein that is able to bind heme with high affinity. It sequesters heme in an inert non-toxic form and transports it to the liver for catabolism and excretion.<ref name="Schaer Vinchi Ingoglia Tolosano p. "/>