Role of intestinal mucins in innate host defense mechanisms against pathogens

Abstract

Gastrointestinal mucins produced by goblet cells comprise the main structural components of the mucus layer. Mucins play a critical role in the maintenance of mucosal homeostasis and are responsible for the differential effector and regulatory responses against a plethora of microorganisms, including commensals and pathogens. In this review, we present a comprehensive overview on mucin biology, its properties, classification and gene assembly. We also consider the structure of the mucin gene, its proteins and its role in innate host defenses. We compare the various mucin secretagogues and the differential regulatory pathways involved in mucin biosynthesis and secretion during normal and diverse pathogenic conditions. Finally, we summarize the putative uncharted aspects of mucin-derived innate host defenses, whose exploration will help drug developers to identify factors that can strengthen mucosal integrity and will facilitate basic science research into curative treatments for gastrointestinal diseases.

Fig. 1

Modulation of MUC2 expression by inflammatory mediators and mucin secretagogues. Pro- and anti-inflammatory cytokines differentially activate the SAPK/JNK or the JAK/STAT pathways while mucin secretagogues cause cAMP-mediated activation of CREB. RA = retinoic acid; RAR = retinoic acid receptor; AC = adenylate cyclase; PKA = protein kinase A; CREB = cAMP-responsive element; SAPK/JNK = stress-activated protein kinase/c-Jun NH2-terminal kinase; JAK = janus kinase; STAT = signal transducers and activators of transcription.

Fig. 2

General organization of a MUC2 promoter and the location of identified cis-acting elements. NF-κB is the final effector molecule in multiple pathways involved in mucin regulation. Spl, p53 and other transcription factors bind at various GC-rich boxes in the promoter region. Location is numerically denoted relative to the AUG (+1) translation codon. C/EBP = CCAAT/enhancer binding protein; NF-κB = nuclear factor κB; CDX2 = caudal-type homeobox transcription factor-2.

Fig. 3

Modulation of mucin expression by components of Gram-negative and Gram-positive bacteria. LTA binds to host surface through platelet-activating factor receptor while LPS from Gram-negative bacteria bind through LBP and Toll-like receptors. Both the pathways converge at Ras and lead to the activation of NF-κB and mucin production. Bacterial flagellin signals through binding to glycolipid Asialo-GM1. This stimulates the release of ATP which finally causes an increase in the level of intracellular calcium and stimulates downstream pathways. Binding to Toll-like receptors may also activate a sequence of signals involving PKC, DUOX1, ROS, TACE and EGFR activation, leading to downstream signaling. LTA = lipoteichoic acid; LPS = lipopolysaccharides; PAFR = platelet-activating factor receptor; LBP = LPS-binding protein; G = G protein; ADAM10 = a disintegrin and metalloproteinase domain 10; HB-EGF = heparin-binding EGF-like growth factor; MAPK = mitogen-activated protein kinase; ERK = extracellular regulated kinase; MEK = MAPK ERK kinase; PKC = protein kinase C; DUOX1 = dual oxidase 1; ROS = reactive oxygen species; TACE = tumor necrosis factor-a-converting enzyme; EGFR = epidermal growth factor receptor; TGF-α = transforming growth factor-α.