Goblet cells: guardians of gut immunity and their role in gastrointestinal diseases

Abstract

Goblet cells (GCs) are specialised guardians lining the intestine. They play a critical role in gut defence and immune regulation. GCs continuously secrete mucus creating a physical barrier to protect from pathogens while harbouring symbiotic gut bacteria adapted to live within the mucus. GCs also form specialised GC-associated passages in a dynamic and regulated manner to deliver luminal antigens to immune cells, promoting gut tolerance and preventing inflammation. The composition of gut bacteria directly influences GC function, highlighting the intricate interplay between these components of a healthy gut. Indeed, imbalances in the gut microbiome can disrupt GC function, contributing to various gastrointestinal diseases like colorectal cancer, inflammatory bowel disease, cystic fibrosis, pathogen infections and liver diseases. This review explores the interplay between GCs and the immune system. We delve into the underlying mechanisms by which GC dysfunction contributes to the development and progression of gastrointestinal diseases. Finally, we examine current and potential treatments that target GCs and represent promising avenues for further investigation.

Figure 1. Goblet cells functions. Goblet cells (GCs) play a multifaceted role in the mucosal immune system, including (A) Mucin secretion: GCs constantly produce mucins forming a protective gel layer on the surface of the intestine. This mucus barrier acts as a first line of defence, trapping pathogens and preventing them from reaching the underlying tissues. Under normal circumstances, the thickness of this gel remains upheld through continuous mucin secretion. Nevertheless, when the gut faces challenges such as microbial intrusion or harsh stimuli, GCs undergo stimulation to accelerate mucin release. Both, physiological or pathological stimuli, result in a marked increase in intracellular calcium ions (Ca²⁺)-triggered stimulated mucus secretion. Various factors like neuropeptides, cytokines and lipids further influence the stimulated mucin release. On acetylcholine (ACh) exposure, the activation of muscarinic ACh receptor 1 (mAChR1) also triggers the mobilisation of Ca²⁺ from intracellular reserves contributing to mucus secretion and effectively displacing pathogens from the gut lining. (B) Other secretory functions: The release of chemokines and cytokines initiates and strengthens Th2 responses facilitating tissue repair and attracting effector cells that perform functions crucial to innate immunity extending beyond mere barrier maintenance. GCs also discharge antimicrobial peptides (AMPs) including resistin-like molecule ß, regenerating islet-derived 3 proteins and trefoil factor which effectively eliminate commensal bacteria and pathogens that breach the mucus layer. (C) GC-associated antigen passages (GAPs): Activation of mAChR4 by ACh initiates a process termed fluid-phase bulk endocytosis culminating in the formation of GAPs in the small intestine. Endocytic vesicles containing luminal fluid-phase cargo are transported through the cell for degradation, membrane recycling and transcytosis. This allows the cargo to be acquired by lamina propria dendritic cells (LP-DCs). The main LP-DCs subset subadjacent to GAPs is the CD103⁺CX3CR1⁻ subset and possesses preferential tolerogenic properties. Created with BioRender.com. E.R., endoplasmic reticulum; IEC, intestinal epithelial cells.

Figure 2. Gastrointestinal disorders impacting goblet cell (GC) function. The malfunction of GCs, marked by changes in numbers, abnormal differentiation and modified mucin production, plays a substantial role in the onset and advancement of various gastrointestinal disorders. These include inflammatory bowel disease, colorectal cancer, mucinous adenocarcinoma, pathogen infections, cystic fibrosis and liver diseases. Understanding the mechanisms behind these disruptions is essential for devising targeted therapies aimed at reinstating GC function and enhancing overall gut health. Created with BioRender.com. CLCA1, calcium-activated chloride channel regulator 1; FCGBP, Fc-binding protein; GAP, GC-associated antigen passage; IL-18, interleukin 18; MUC2, mucin 2; RELM-β, resistin-like molecule β; TFF3, trefoil factor 3; ZG16, Zymogen granule protein 16.