Intestinal commensal microbiota and cytokines regulate Fut2+ Paneth cells for gut defense

Paneth cells are intestinal epithelial cells that release antimicrobial peptides, such as α-defensin as part of host defense. Together with mesenchymal cells, Paneth cells provide niche factors for epithelial stem cell homeostasis. Here, we report two subtypes of murine Paneth cells, differentiated by their production and utilization of fucosyltransferase 2 (Fut2), which regulates α(1,2)fucosylation to create cohabitation niches for commensal bacteria and prevent invasion of the intestine by pathogenic bacteria. The majority of Fut2− Paneth cells were localized in the duodenum, whereas the majority of Fut2+ Paneth cells were in the ileum. Fut2+ Paneth cells showed higher granularity and structural complexity than did Fut2− Paneth cells, suggesting that Fut2+ Paneth cells are involved in host defense. Signaling by the commensal bacteria, together with interleukin 22 (IL-22), induced the development of Fut2+ Paneth cells. IL-22 was found to affect the α-defensin secretion system via modulation of Fut2 expression, and IL-17a was found to increase the production of α-defensin in the intestinal tract. Thus, these intestinal cytokines regulate the development and function of Fut2+ Paneth cells as part of gut defense.

Therapeutic Opportunities of IL-22 in Non-Alcoholic Fatty Liver Disease: From Molecular Mechanisms to Clinical Applications

Nonalcoholic fatty liver disease (NAFLD) represents one of the most common liver disorders and can progress into a series of liver diseases, including nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and even liver cancer. Interleukin-22 (IL-22), a member of the IL-10 family of cytokines, is predominantly produced by lymphocytes but acts exclusively on epithelial cells. IL-22 was proven to favor tissue protection and regeneration in multiple diseases. Emerging evidence suggests that IL-22 plays important protective functions against NAFLD by improving insulin sensitivity, modulating lipid metabolism, relieving oxidative and endoplasmic reticulum (ER) stress, and inhibiting apoptosis. By directly interacting with the heterodimeric IL-10R2 and IL-22R1 receptor complex on hepatocytes, IL-22 activates the Janus kinase 1 (JAK1)/ signal transducer and activator of transcription 3 (STAT3), c-Jun N-terminal kinase (JNK) and extracellular-signal regulated kinase (ERK) pathways to regulate the subsequent expression of genes involved in inflammation, metabolism, tissue repair, and regeneration, thus alleviating hepatitis and steatosis. However, due to the wide biodistribution of the IL-22 receptor and its proinflammatory effects, modifications such as targeted delivery of IL-22 expression and recombinant IL-22 fusion proteins to improve its efficacy while reducing systemic side effects should be taken for further clinical application. In this review, we summarized recent progress in understanding the physiological and pathological importance of the IL-22-IL-22R axis in NAFLD and the mechanisms of IL-22 in the protection of NAFLD and discussed the potential strategies to maneuver this specific cytokine for therapeutic applications for NAFLD.

Exposure to combustion derived particulate matter exacerbates influenza infection in neonatal mice by inhibiting IL22 production

Background Particulate matter (PM) containing environmentally persistent free radicals (EPFRs) are formed during various combustion processes, including the thermal remediation of hazardous wastes. Exposure to PM adversely affects respiratory health in infants and is associated with increased morbidity and mortality due to acute lower respiratory tract infections. We previously reported that early-life exposure to PM damages the lung epithelium and suppresses immune responses to influenza virus (Flu) infection, thereby enhancing Flu severity. Interleukin 22 (IL22) is important in resolving lung injury following Flu infection. In the current study, we determined the effects of PM exposure on pulmonary IL22 responses using our neonatal mouse model of Flu infection. Results Exposure to PM resulted in an immediate (0.5–1-day post-exposure; dpe) increase in IL22 expression in the lungs of C57BL/6 neonatal mice; however, this IL22 expression was not maintained and failed to increase with either continued exposure to PM or subsequent Flu infection of PM-exposed mice. This contrasts with increased IL22 expression in age-matched mice exposed to vehicle and Flu infected. Activation of the aryl hydrocarbon receptor (AhR), which mediates the induction and release of IL22 from immune cells, was also transiently increased with PM exposure. The microbiome plays a major role in maintaining epithelial integrity and immune responses by producing various metabolites that act as ligands for AhR. Exposure to PM induced lung microbiota dysbiosis and altered the levels of indole, a microbial metabolite. Treatment with recombinant IL22 or indole-3-carboxaldehyde (I3A) prevented PM associated lung injury. In addition, I3A treatment also protected against increased mortality in Flu-infected mice exposed to PMs. Conclusions Together, these data suggest that exposure to PMs results in failure to sustain IL22 levels and an inability to induce IL22 upon Flu infection. Insufficient levels of IL22 may be responsible for aberrant epithelial repair and immune responses, leading to increased Flu severity in areas of high PM.

Functions of 1,25-dihydroxy vitamin D3, vitamin D3 receptor and interleukin-22 involved in pathogenesis of gout arthritis through altering metabolic pattern and inflammatory responses

Background Gouty arthritis (GA) is a common type of inflammatory arthritis. Recent studies demonstrated that 1,25-dihydroxy vitamin D3 (1,25(OH) 2 VD3) and vitamin D3 receptor (VD-R) play a protective role in acute inflammation, but interleukin-22(IL-22) promotes inflammation, especially for arthritis. However, our understanding of the responses of 1,25(OH) 2VD3 and IL-22 to gout was still unclear. Presently, in-depth metabolomics, bioinformatics and clinical characteristics analyses were performed to elucidate the pathogenesis and valuable clinical indicators of gouty arthritis. Methods Peripheral venous blood was taken for investigation. The levels of IL-22 and 1,25(OH)2VD3 were determined in patient’s plasma via ELISA, and the mRNA levels of IL-22 and VD-R were measured via qRT-PCR. The interaction network of VD-R and IL22 were constructed by the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING), and the biological function of the related proteins were analyzed by Clusterprofiler Metabolomics were performed to decipher the metabolic variations of GA. Results The levels of VD-R and 1,25(OH) 2 VD3 were identified to be low. What,s more, GA patients were reported to have high expression of IL-22. And IL-22 levels positively correlated with C-reactiveprotein (CRP) serum levels in the bivariate correlation analysis, whereas the level of 1,25(OH) 2VD3 negatively correlated with that of CRP. GO and KEGG analyses revealed that IL-22 and 1,25(OH) 2 VD3 were involved in stress immunity and inflammatory responses. These pathways are known to play a role in GA pathogenesis. Meanwhile, the metabolic profiles of GA serum showed that the increase in various amino acids and uric acid are involved in GA pathogenesis. Importantly, VD-R and IL22 closely correlated with the level of key metabolites uric acid, whose increase promoted the occurrence of GA. Conclusion GA patients have low levels of VD-R and 1,25(OH) 2 VD3, and high levels of IL-22 together with various amino acids and uric acid. The levels of IL-22 and 1,25(OH) 2VD3 were positively and negatively correlated with C-reactive protein (CRP) serum levels, respectively. Both IL-22 and 1,25(OH) 2 VD3 functioned in GA-related immune and inflammatory responses, and closely correlated with the level of GA-related uric acid. Overall, IL-22, VD-R and 1,25(OH) 2 VD3 play functionally important roles in inflammatory responses and are relevant to gout pathogenesis.

Interleukin-22 attenuates allergic airway inflammation in ovalbumin-induced asthma mouse model

Background Allergic asthma is a chronic airway inflammatory disease with a number of cytokines participating in its pathogenesis and progress. Interleukin (IL)-22, which is derived from lymphocytes, acts on epithelial cells and play a role in the chronic airway inflammation. However, the actual role of IL-22 in allergic asthma is still unclear. Therefore, we explored the effect of IL-22 on allergic airway inflammation and airway hyperresponsiveness (AHR) in an ovalbumin (OVA)-induced asthma mouse model. Methods To evaluate the effect of IL-22 in an allergic asthma model, BALB/c mice were sensitized and challenged with OVA; then the recombinant mouse IL-22 was administered intranasally 24 h prior to each challenge. The IL-22 levels in lung homogenates and bronchoalveolar lavage fluid (BALF) were measured by enzyme linked immunosorbent assay, respectively. AHR was evaluated through indicators including airways resistance (Rrs), elastance (Ers) and compliance (Crs); the inflammatory cell infiltration was assessed by quantification of differential cells counts in BALF and lung tissues stained by hematoxylin and eosin (H&E); IL-22 specific receptors were determined by immunohistochemistry staining. Results The concentration of IL-22 was significantly elevated in the OVA-induced mice compared with the control mice in lung homogenates and BALF. In the OVA-induced mouse model, IL-22 administration could significantly attenuate AHR, including Rrs, Ers and Crs, decrease the proportion of eosinophils in BALF and reduce inflammatory cell infiltration around bronchi and their concomitant vessels, compared with the OVA-induced group. In addition, the expression of IL-22RA1 and IL-10RB in the lung tissues of OVA-induced mice was significantly increased compared with the control mice, while it was dramatically decreased after the treatment with IL-22, but not completely attenuated in the IL-22-treated mice when compared with the control mice. Conclusion Interleukin-22 could play a protective role in an OVA-induced asthma model, by suppressing the inflammatory cell infiltration around bronchi and their concomitant vessels and airway hyperresponsiveness, which might associate with the expression of its heterodimer receptors. Thus, IL-22 administration might be an effective strategy to attenuate allergic airway inflammation.