IL-22 Upregulates Epithelial Claudin-2 to Drive Diarrhea and Enteric Pathogen Clearance

Abstract

SUMMARY Diarrhea is a host response to enteric pathogens, but its impact on pathogenesis remains poorly defined. By infecting mice with the attaching and effacing bacteria Citrobacter rodentium, we defined the mechanisms and contributions of diarrhea and intestinal barrier loss to host defense. Increased permeability occurred within 2 days of infection and coincided with IL-22-dependent upregulation of the epithelial tight junction protein claudin-2. Permeability increases were limited to small molecules, as expected for the paracellular water and Na+ channel formed by claudin-2. Relative to wildtype, claudin-2-deficient mice experienced severe disease, including increased mucosal colonization by C. rodentium, prolonged pathogen shedding, exaggerated cytokine responses, and greater tissue injury. Conversely, transgenic claudin-2 overexpression reduced disease severity. Chemically-induced osmotic diarrhea reduced colitis severity and C. rodentium burden in claudin-2 deficient, but not transgenic, mice, demonstrating that claudin-2-mediated protection is the result of enhanced water efflux. Thus, IL-22-induced claudin-2 upregulation drives diarrhea and pathogen clearance.

Innate lymphoid cells, mediators of tissue homeostasis, adaptation and disease tolerance

“…Early after infection with C. rodentium (and potentially also upon infection by other attaching‐and‐effacing bacteria) an IL‐22‐dependent innate immune response leads to upregulation of claudin‐2 expression in the colonic epithelium, resulting in efflux of water into the lumen, enabling a swift diarrheal response which expedites bacterial clearance . Importantly, C. rodentium infection also promotes processes leading to leak of larger substances, including bidirectional, unrestricted leak stemming from damage to the epithelial layer.…”

Intestinal epithelial cells: at the interface of the microbiota and mucosal immunity

“…IL‐22 also affects the glycosylation of IEC surface proteins by inducing fucosyltransferase 2 (Fut2) expression, thereby enhancing host protection against Salmonella Typhimurium . Mucin production by IECs is also increased by IL‐22 through the activation of signal transducer and activator of transcription STAT3, and tight junction proteins such as claudin‐2 have recently been shown to be up‐regulated by IL‐22, inducing diarrhoea and facilitating clearance of Citrobacter rodentium in a mouse model of enteric infection …”

“…99 Mucin production by IECs is also increased by IL-22 through the activation of signal transducer and activator of transcription STAT3, 100 and tight junction proteins such as claudin-2 have recently been shown to be up-regulated by IL-22, inducing diarrhoea and facilitating clearance of Citrobacter rodentium in a mouse model of enteric infection. 101 Beyond ILC3s and IL-22, some other lymphoid cells also contribute to IEC responses. During parasitic infection, IECs secrete a number of cytokines that promote the expansion and activation of group 2 innate lymphoid cells (ILC2s) and basophils, including IL-33 and thymic stromal lymphopoietin (TSLP), and IL-25 produced by tuft cells.…”

Claudin reduction may relate to an impaired skin barrier in rosacea

“…Previous studies have revealed the important role of certain CLDN in physiological regulation of junction permeability in a variety of tissues, and the epithelial barrier dysfunction, resulting from deficiency of CLDN, plays a crucial role in the development of various disorders (e.g. atopic dermatitis) . However, no study has yet examined the expression of CLDN in lesional skin of patients with rosacea, or investigated the correlation between CLDN and the development of rosacea.…”

“…atopic dermatitis). 20,[23][24][25] However, no study has yet examined the expression of CLDN in lesional skin of patients with rosacea, or investigated the correlation between CLDN and the development of rosacea. Therefore, the aim of this study was to describe the expression of CLDN in lesional skin of patients with rosacea compared with healthy skin, and determine the possible relationship between CLDN and the development of rosacea.…”