The liver isoform of the enzyme alkaline phosphatase (AP) has been used classically as a serum biomarker for hepatic disease states such as hepatitis, steatosis, cirrhosis, drug-induced liver injury, and hepatocellular carcinoma. Recent studies have demonstrated a more general anti-inflammatory role for AP, as it is capable of dephosphorylating potentially deleterious molecules such as nucleotide phosphates, the pathogenic endotoxin lipopolysaccharide (LPS), and the contact clotting pathway activator polyphosphate (polyP), thereby reducing inflammation and coagulopathy systemically. Yet the mechanism underlying the observed increase in liver AP levels in circulation during inflammatory insults is largely unknown. This paper hypothesizes an immunological role for AP in the liver and the potential of this system for damping generalized inflammation along with a wide range of ancillary pathologies. Based on the provided framework, a mechanism is proposed in which AP undergoes transcytosis in hepatocytes from the canalicular membrane to the sinusoidal membrane during inflammation and the enzyme's expression is upregulated as a result. Through a tightly controlled, nucleotide-stimulated negative feedback process, AP is transported in this model as an immune complex with immunoglobulin G by the asialoglycoprotein receptor through the cell and secreted into the serum, likely using the receptor's State 1 pathway. The subsequent dephosphorylation of inflammatory stimuli by AP and uptake of the circulating immune complex by endothelial cells and macrophages may lead to decreased inflammation and coagulopathy while providing an early upstream signal for the induction of a number of anti-inflammatory gene products, including AP itself.
Keywords: ADP; AE2; AMP; AP; ASGP-R; ASOR; ATP; Ala; Alkaline phosphatase; Arg; Asialoglycoprotein receptor; Asn; BDL; CABG; CFTR; CRD; CURL; Coagulation; Cys; DAMP; DIC; FVIII; Fab; Fc; Fc gamma receptor; Fc gamma receptor IIb; FcRn; FcγR; FcγRIIb; GCAP; GPI; Gly; IAP; IFγ; IL-1; IL-2; IL-6; IMCD; IgA; IgG; Immunoglobulin G; Inflammation; LPS; LRC; LSECs; Liver; MDCK; MHC; Madin–Darby canine kidney cells; PAMP; PLAP; PLC; PLD; PRR; Phe; R-ASGP-R; SIRS; Ser; TGN; TLR; TNAP; TNF; TNFα; TfR; Toll-like receptor; Tyr; adenosine diphosphate; adenosine monophosphate; adenosine triphosphate; alanine; alkaline phosphatase; anion exchanger 2; arginine; asialoglycoprotein receptor; asialoorosomucoid; asparagine; biAP; bile duct ligation; bovine intestinal AP; cAMP; carbohydrate recognition domain; compartment for uncoupling of receptor and ligand; coronary artery bypass graft; cyclic AMP; cysteine; cystic fibrosis transmembrane conductance regulator; damage-associated molecular pattern; disseminated intravascular coagulation; factor VIII; fragment, antigen-binding; fragment, crystallizable; germ-cell AP; glycine; glycosylphosphatidylinositol; immunoglobulin A; immunoglobulin G; inner medullary collecting duct cells; interferon gamma; interleukin-1; interleukin-2; interleukin-6; intestinal AP; ligand–receptor complex; lipopolysaccharide; liver sinusoidal endothelial cells; major histocompatibility complex; neonatal Fc receptor; pIgA; pIgR; pathogen-associated molecular pattern; pattern-recognition receptor; phenylalanine; phospholipase C; phospholipase D; placental AP; polyP; polymeric IgA; polymeric immunoglobulin receptor; polyphosphatase; rescue ASGP-R; serine; systemic inflammatory response syndrome; tissue necrosis factor; tissue necrosis factor alpha; tissue non-specific AP; trans-Golgi network; transferrin receptor; tyrosine; vWF; von Willebrand factor.