A cytokine network involving IL-36γ, IL-23, and IL-22 promotes antimicrobial defense and recovery from intestinal barrier damage

Abstract

The gut epithelium acts to separate host immune cells from unrestricted interactions with the microbiota and other environmental stimuli. In response to epithelial damage or dysfunction, immune cells are activated to produce interleukin (IL)-22, which is involved in repair and protection of barrier surfaces. However, the specific pathways leading to IL-22 and associated antimicrobial peptide (AMP) production in response to intestinal tissue damage remain incompletely understood. Here, we define a critical IL-36/IL-23/IL-22 cytokine network that is instrumental for AMP production and host defense. Using a murine model of intestinal damage and repair, we show that IL-36γ is a potent inducer of IL-23 both in vitro and in vivo. IL-36γ-induced IL-23 required Notch2-dependent (CD11bCD103) dendritic cells (DCs), but not Batf3-dependent (CD11bCD103) DCs or CSF1R-dependent macrophages. The intracellular signaling cascade linking IL-36 receptor (IL-36R) to IL-23 production by DCs involved MyD88 and the NF-κB subunits c-Rel and p50. Consistent with in vitro observations, IL-36R- and IL-36γ-deficient mice exhibited dramatically reduced IL-23, IL-22, and AMP levels, and consequently failed to recover from acute intestinal damage. Interestingly, impaired recovery of mice deficient in IL-36R or IL-36γ could be rescued by treatment with exogenous IL-23. This recovery was accompanied by a restoration of IL-22 and AMP expression in the colon. Collectively, these data define a cytokine network involving IL-36γ, IL-23, and IL-22 that is activated in response to intestinal barrier damage and involved in providing critical host defense.

Setting off the Alarms:Candida albicansElicits Pro-Inflammatory Differential Gene Expression in Intestinal Peyer’s Patches

“…3A) . These cytokines are known to play important roles in maintaining barrier integrity and in antifungal immunity (24). In particular, IL-22, is a key cytokine that has been demonstrated to increase gut epithelial and immune barrier functions by inducing antimicrobial activity, as well as stimulating tissue-damage protection and tissue repair and remodeling, suggesting that PPs recognize all three microbes as a potential threat (25).…”

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

“…For example, in response to microbial metabolites such as tryptophan catabolites, type 3 innate lymphoid cells (ILC3s) produce cytokines that regulate barrier functions of IECs . ILC3s secrete IL‐22, which promotes IEC homeostasis and repair, and can induce AMPs to control the growth of both pathogenic and commensal microbes . IL‐22 also affects the glycosylation of IEC surface proteins by inducing fucosyltransferase 2 (Fut2) expression, thereby enhancing host protection against Salmonella Typhimurium .…”

“…25 ILC3s secrete IL-22, which promotes IEC homeostasis and repair, and can induce AMPs to control the growth of both pathogenic and commensal microbes. [96][97][98] IL-22 also affects the glycosylation of IEC surface proteins by inducing fucosyltransferase 2 (Fut2) expression, thereby enhancing host protection against Salmonella Typhimurium. 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.…”

Advancing the therapeutic potential of the IL‐1 family in inflammatory diseases – Meeting report

“…Whether IL‐36 can drive proinflammatory or proresolving mechanisms in intestinal inflammation is dependent on the acute or chronic nature of the experimental models employed, as well as the type of pathogenic cellular responses under analysis. While IL‐36γ acts to promote epithelial barrier resolution in the innate DSS model of disease, it can also act to enhance pathogenic Th9 responses and restrict Treg function in the gut leading to an exacerbated disease phenotype in a T cell dependent model . The pathogenic nature of IL‐36 driven intestinal T cell responses were also highlighted by Pat Walsh (Trinity College Dublin), who also described how IL‐36 cytokines can alter the composition of the intestinal microbiome which may account, at least in part, for the apparent opposing roles of these cytokines in gut homeostasis and inflammation .…”