Intestinal goblet cells sample and deliver lumenal antigens by regulated endocytic uptake and transcytosis.

Jenny K Gustafsson,Devesha H Kulkarni,Kathryn A Knoop,Jazmyne E Davis,Wayne I Lencer,Tracy Rappai,James Aj Fitzpatrick,Keely G Mcdonald,Rodney D Newberry,Simon P Hogan

doi:10.7554/elife.67292

Abstract

Intestinal goblet cells maintain the protective epithelial barrier through mucus secretion and yet sample lumenal substances for immune processing through formation of goblet cell associated antigen passages (GAPs). The cellular biology of GAPs and how these divergent processes are balanced and regulated by goblet cells remains unknown. Using high-resolution light and electron microscopy, we found that in mice, GAPs were formed by an acetylcholine (ACh)-dependent endocytic event remarkable for delivery of fluid-phase cargo retrograde into the trans-golgi network and across the cell by transcytosis - in addition to the expected transport of fluid-phase cargo by endosomes to multi-vesicular bodies and lysosomes. While ACh also induced goblet cells to secrete mucins, ACh-induced GAP formation and mucin secretion were functionally independent and mediated by different receptors and signaling pathways, enabling goblet cells to differentially regulate these processes to accommodate the dynamically changing demands of the mucosal environment for barrier maintenance and sampling of lumenal substances.

Highlights

The simple columnar epithelium lining the gastrointestinal tract is an expansive surface exposed to lumenal contents containing innocuous substances from the diet and potentially harmful microbes and their products
To elucidate the cellular mechanism underlying goblet cell associated antigen passages (GAPs) formation and function, we studied the intestines of mice one hour after administration of fluorescent dextran to the gut lumen
The appearance of GAPs on two-photon in vivo imaging (Figure 1A) and on wide-field fluorescence microscopy (Figure 1B) of the small intestine (SI) suggested that the goblet cell cytoplasm was filled with lumenal substances, consistent with passive diffusion of dextran into the cytosol through apical membrane tears following ACh induced mucus granule secretion

Summary

Introduction

The simple columnar epithelium lining the gastrointestinal tract is an expansive surface exposed to lumenal contents containing innocuous substances from the diet and potentially harmful microbes and their products. Underneath and within this epithelium lies the largest collection of immune cells in the body. GAP formation and the delivery of lumenal substances to the immune compartment are closely regulated to prevent inflammatory responses to gut bacteria and dietary antigens in settings where the secretion of mucus to maintain the barrier is critical (Knoop, Gustafsson, McDonald, Kulkarni, Coughlin, et al, 2017; Knoop, McDonald, Kulkarni, & Newberry, 2016; Kulkarni et al, 2018). In response to the same stimulus, goblet cells perform two, but apparently opposing, central roles in intestinal immunity

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Discussion

Conclusion