Epithelial cells: liaisons of immunity

Abstract

The surface and lining tissues of our body are exposed to the external environment, and as such these epithelial tissues must form structural barriers able to defend against microbes, environmental toxins, and mechanical stress. Their cells are equipped to detect a diverse array of surface perturbations, and then launch signaling relays to the immune system. The aim of these liaisons is to coordinate the requisite immune cell response needed to preserve and/or restore barrier integrity and defend the host. It has been recently appreciated that epithelial cells learn from these experiences. Following inflammatory exposure, long-lived stem cells within the tissue retain an epigenetic memory that endows them with heightened responsiveness to subsequent encounters with stress. Here, we review the recent literature on how epithelial cells sense signals from microbes, allergens, and injury at the tissue surface, and transmit this information to immune cells, while embedding a memory of the experience within their chromatin.

Figure 1

Simplified schematic of epithelial tissues of the skin, lung, and small intestine. The skin is composed of epidermis (outer) and dermis (inner) layers. The epidermis is a stratified epithelium maintained and replenished by epithelial stem cells that reside in the innermost layer in contact with the basement membrane. Hair follicles form an orifice to the external environment, extend into the dermis, and are maintained by stem cells in the bulge that activate to generate new hairs. The sebaceous gland secretes sebum containing antimicrobial properties into the hair follicle orifice to prevent pathogen infiltration. In the lungs, the extrapulmonary tissue is a stratified epithelium that transitions to a simple epithelium further down the respiratory tree. Basal cells in these layers are able to generate the different specialized cell types of the lung epithelium. In the intestine, stem cells reside in the crypt, where they self-renew or differentiate into the various cell types of the intestine including Paneth cells, Tuft cells, and Goblet cells. Created with BioRender.com.

Figure 2

Epithelial initiated immune cell crosstalk in response to microbes, environmental factors/allergens and injury. (a) Microbes largely fall into two categories: commensals and pathogens, where each elicits a variety of responses from epithelial cells. Commensals instruct epithelial cell behavior through release of microbial proteins or metabolites. The epithelial cells in turn communicate this information to immune cells through MHCII, release of specific cytokines, or metabolites. In the event of pathogen invasion, epithelial cells are equipped with an arsenal of pattern recognition receptors (PRR) that allow detection of a variety of molecular signatures both at the extracellular membrane and within the cytosol. This information sets off signaling cascades that results in epithelial release of antimicrobial peptides and alarmins that signal to the immune system for help. (b) Environmental factors including dietary metabolites and allergens are detected by epithelial cells through internal sensors such as arylhydrocarbon receptor (AhR), membrane-bound toll like receptors (TLR), or through weakening of intercellular junctional proteins. Detection of these environmental cues leads to a transcriptional response that mounts host defenses including release of cytokines and chemokines that recruit and promote the expansion of a variety of immune cells. (c) Injuries result in a strong proliferative and migratory response within epithelial cells to reinstate barrier integrity. Epithelial cells detect barrier breaches through a variety of mechanisms including loss of intercellular junctions, Notch signaling, or presence of self-DNA within the cytosol. Immune cells are recruited and work together with epithelial cells to rapidly reseal the barrier breach. Created with BioRender.com

Figure 3

Epithelial stem cells retain a memory of inflammation. Epithelial stem cells are routinely exposed to inflammatory stimuli ranging from microbes, virus, injury and environmental factors. During an inflammatory response, inflammation-induced transcription factors facilitate chromatin remodeling resulting in increased chromatin accessibility. Upon resolution, epithelial stem cells retain inflammation-induced chromatin accessibility, but how these loci are maintained remains unknown. Perhaps it is the coupling of homoeostatic transcription factor binding with other epigenetic features such as histone modifications and DNA methylation? During a secondary challenge, stem cells have an increased transcriptional response which in the case of skin epithelial stem cells results in enhanced wound repair and in the case of airway epithelial progenitors propagates chronic inflammation. Further investigation is needed into the inflammation-induced epigenetic and cellular changes within epithelial progenitors and their contribution to inflammatory memory. Created with BioRender.com.