Abstract
Intestinal alkaline phosphatase (IAP) is a multi-functional protein that has been demonstrated to primarily protect the gut. The role of IAP in maintaining intestinal homeostasis is underscored by the observation that IAP expression is defective in many gastrointestinal-related disorders such as inflammatory bowel disease IBD, necrotizing enterocolitis, and metabolic syndrome and that exogenous IAP supplementation improves the outcomes associated with these disorders. Additionally, studies using transgenic IAP-knock out (IAP-KO) mouse models further support the importance of the defensive role of IAP in the intestine. Supplementation of exogenous IAP and cellular overexpression of IAP have also been used in vitro to dissect out the downstream mechanisms of this protein in mammalian cell lines. Some of the innate immune functions of IAP include lipopolysaccharide (LPS) detoxification, protection of gut barrier integrity, regulation of gut microbial communities and its anti-inflammatory roles. A novel function of IAP recently identified is the induction of autophagy. Due to its critical role in the gut physiology and its excellent safety profile, IAP has been used in phase 2a clinical trials for treating conditions such as sepsis-associated acute kidney injury. Many excellent reviews discuss the role of IAP in physiology and pathophysiology and here we extend these to include recent updates on this important host defense protein and discuss its role in innate immunity via its effects on bacteria as well as on host cells. We will also discuss the relationship between IAP and autophagy and how these two pathways may act in concert to protect the gut.
Highlights
Intestinal alkaline phosphatase (IAP) is a member of the alkaline phosphatase family and is one of the four types known to exist in humans: tissue non-specific alkaline phosphatase (TNAP), placental alkaline phosphatase (PLAP), germ cell alkaline phosphatase (GCALP), and intestinal alkaline phosphatase (IAP)
Many functions far have been ascribed to IAP: (1) IAP detoxifies lipopolysaccharide (LPS) [5], which is responsible for causing gut permeability and inflammation; (2) IAP dephosphorylates pro-inflammatory nucleotides such as adenosine triphosphate (ATP) and uridine triphosphate (UDP) [6]; (3) IAP
These include: (1) the physical epithelial barrier constructed by tight junction proteins (TJPs), adherent junction proteins (AJPs), and desmosomes which prevents paracellular flux and microbial translocation; (2) the mucus layer, comprised of various O-linked glycoproteins called mucins, which acts as a partition between the bacteria and the epithelium and prevents their translocation into the epithelium; (3) antimicrobial peptides and proteins such as lysozyme that kill microbes, controlling their numbers in the intestinal lumen; (4) IAP, which protects the barrier directly from harmful effects of LPS and indirectly by orchestrating the other three mechanisms of the first line of defense
Summary
Intestinal alkaline phosphatase (IAP) is a member of the alkaline phosphatase family and is one of the four types known to exist in humans: tissue non-specific alkaline phosphatase (TNAP), placental alkaline phosphatase (PLAP), germ cell alkaline phosphatase (GCALP), and intestinal alkaline phosphatase (IAP). (2) IAP dephosphorylates pro-inflammatory nucleotides such as ATP and UDP [6]; (3) IAP regulates bicarbonate secretion and maintains duodenal pH [7]; (4) IAP protects the intestinal epithelial barrier by regulating the level of tight junction proteins such as occludins, claudins, and zonula occludens [8]; (5) IAP regulates gut microbial communities [9]; (6) IAP appears to positively regulate antimicrobial proteins such as lysozymes that control the bacterial numbers in the intestine [10]; (7) IAP induces autophagy [10], a vital innate immune pathway known for its role in barrier function, inflammation, and its antimicrobial. We discuss in detail current advances in understanding the innate immune functions of IAP that serve to protect the intestinal epithelium. We will discuss the relationship between IAP and autophagy and how these two important innate immune pathways may orchestrate downstream events to defend the gut at multiple levels
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