Group 3 Innate Lymphoid Cells Program a Distinct Subset of IL-22BP-Producing Dendritic Cells Demarcating Solitary Intestinal Lymphoid Tissues.

Solitary intestinal lymphoid tissues such as cryptopatches (CPs) and isolated lymphoid follicles (ILFs) constitute steady-state activation hubs containing group 3 innate lymphoid cells (ILC3) that continuously produce interleukin (IL)-22. The outer surface of CPs and ILFs is demarcated by a poorly characterized population of CD11c+ cells. Using genome-wide single-cell transcriptional profiling of intestinal mononuclear phagocytes and multidimensional flow cytometry, we found that CP- and ILF-associated CD11c+ cells were a transcriptionally distinct subset of intestinal cDCs, which we term CIA-DCs. CIA-DCs required programming by CP- and ILF-resident CCR6+ ILC3 via lymphotoxin-ß receptor signaling in cDCs. CIA-DCs differentially expressed genes associated with immunoregulation and were the major cellular source of IL-22 binding protein (IL-22BP) at steady state. Mice lacking CIA-DC-derived IL-22BP exhibited diminished expression of epithelial lipid transporters, reduced lipid resorption, and changes in body fat homeostasis. Our findings provide insight into the design principles of an immunoregulatory checkpoint controlling nutrient absorption.

Hepatic vagotomy blunts liver regeneration after hepatectomy by downregulating the expression of interleukin-22.

BACKGROUND: Rapid regeneration of the residual liver is one of the key determinants of successful partial hepatectomy (PHx). At present, there is a lack of recognized safe, effective, and stable drugs to promote liver regeneration. It has been reported that vagus nerve signaling is beneficial to liver regeneration, but the potential mechanism at play here is not fully understood. AIM: To explore the effect and mechanism of hepatic vagus nerve in liver regeneration after PHx. METHODS: A PHx plus hepatic vagotomy (Hv) mouse model was established. The effect of Hv on liver regeneration after PHx was determined by comparing the liver regeneration levels of the PHx-Hv group and the PHx-sham group mice. In order to further investigate the role of interleukin (IL)-22 in liver regeneration inhibition mediated by Hv, the levels of IL-22 in the PHx-Hv group and the PHx-sham group was measured. The degree of liver injury in the PHx-Hv group and the PHx-sham group mice was detected to determine the role of the hepatic vagus nerve in liver injury after PHx. RESULTS: Compared to control-group mice, Hv mice showed severe liver injury and weakened liver regeneration after PHx. Further research found that Hv downregulates the production of IL-22 induced by PHx and blocks activation of the signal transducer and activator of transcription 3 (STAT3) pathway then reduces the expression of various mitogenic and anti-apoptotic proteins after PHx. Exogenous IL-22 reverses the inhibition of liver regeneration induced by Hv and alleviates liver injury, while treatment with IL-22 binding protein (an inhibitor of IL-22 signaling) reduce the concentration of IL-22 induced by PHx, inhibits the activation of the STAT3 signaling pathway in the liver after PHx, thereby hindering liver regeneration and aggravating liver injury in PHx-sham mice. CONCLUSION: Hv attenuates liver regeneration after hepatectomy, and the mechanism may be related to the fact that Hv downregulates the production of IL-22, then blocks activation of the STAT3 pathway.

IL-18/IL-18BP and IL-22/IL-22BP: Two interrelated couples with therapeutic potential.

Interleukin (IL)-18 and IL-22 are key components of cytokine networks that play a decisive role in (pathological) inflammation, host defense, and tissue regeneration. Tight regulation of cytokine-driven signaling, inflammation, and immunoactivation is supposed to enable nullification of a given deleterious trigger without mediating overwhelming collateral tissue damage or even activating a cancerous face of regeneration. In fact, feedback regulation by specific cytokine opponents is regarded as a major means by which the immune system is kept in balance. Herein, we shine a light on the interplay between IL-18 and IL-22 and their opponents IL-18 binding protein (IL-18BP) and IL-22BP in order to provide integrated information on their biology, pathophysiological significance, and prospect as targets and/or instruments of therapeutic intervention.

Pivotal Role of IL-22 Binding Protein in the Epithelial Autoregulation of Interleukin-22 Signaling in the Control of Skin Inflammation.

Disruption of skin homeostasis can lead to inflammatory cutaneous diseases resulting from the dysregulated interplay between epithelial keratinocytes and immune cells. Interleukin (IL)-22 signaling through membrane-bound IL-22 receptor 1 (IL-22R1) is crucial to maintain cutaneous epithelial integrity, and its malfunction mediates deleterious skin inflammation. While IL-22 binding protein (IL-22BP) binds IL-22 to suppress IL-22 signaling, how IL-22BP controls epithelial functionality to prevent skin inflammation remains unclear. Here, we describe the pivotal role of IL-22BP in mediating epithelial autoregulation of IL-22 signaling for the control of cutaneous pathogenesis. Unlike prominent expression of IL-22BP in dendritic cells in lymphoid tissues, epidermal keratinocytes predominantly expressed IL-22BP in the skin in the steady state, whereas its expression decreased during the development of psoriatic inflammation. Deficiency in IL-22BP aggravates psoriasiform dermatitis, accompanied by abnormal hyperproliferation of keratinocytes and excessive cutaneous inflammation as well as enhanced dermal infiltration of granulocytes and γδT cells. Furthermore, IL-22BP abrogates the functional alternations of keratinocytes upon stimulation with IL-22. On the other hand, treatment with IL-22BP alleviates the severity of cutaneous pathology and inflammation in psoriatic mice. Thus, the fine-tuning of IL-22 signaling through autocrine IL-22BP production in keratinocytes is instrumental in the maintenance of skin homeostasis.

Urinary interleukin 22 binding protein as a marker of lupus nephritis in Egyptian children with juvenile systemic lupus erythematosus.

Juvenile systemic lupus erythematosus (JSLE) is a multi-system autoimmune inflammatory disease. Generally, 60% of patients will develop lupus nephritis (LN); thus, early recognition and treatment is associated with better outcome. Interleukin 22 (IL-22) is involved in tissue inflammation and is regulated by interleukin 22 binding protein (IL-22BP). This study aimed to use IL-22BP as a non-invasive marker for disease activity in JSLE and LN. This is a cross-sectional study conducted on 82 subjects: 51 JSLE patients and 31 healthy controls of matched age and gender. Urinary IL-22BP was measured using enzyme-linked immunosorbent assay, and its level was correlated with different clinical and laboratory data in JSLE as well as Systemic Lupus Erythematous Disease Activity Index 2000 (SLEDAI-2k), renal SLEDAI-2k, and Systemic Lupus International Collaborating Clinics (SLICC) renal activity score which were used to assess overall disease and renal activity. Our results showed that urinary IL-22BP level was significantly higher in JSLE patients with mean level of 4.13 ± 1.10, as compared to controls 1.63 ± 0.61 (P value < 0.001); also, patients with active LN had urinary levels of IL-22BP (5.47 ± 1.03) higher than patients with active JSLE without LN (4.23 ± 0.72) and patients with non-active JSLE/LN (3.5 ± 0.65) with a highly significant P value < 0.001. There was a positive correlation with SLEDAI-2k, renal SLEDAI, and renal activity scores (P < 0.001). Urinary IL-22BP may be used as a non-invasive marker for assessment of disease activity in children with JSLE and LN.

Role of IL-22/IL-22BP axis in hepatic ischemia-reperfusion injury / 中国药理学通报

Aim To investigate the role of 1L-22 / IL- 22BP axis in hepatic ischeniia-reperfusion injury and its potential mechanism.Methods Short, medium, and long-term liver ischemia-reperfusion injury (IKI) and IRI + IL-22 mouse models were established, then the scrum IL-22 concentration, IL-22BP mRNA, IL- 22R a 1 mRNA and STAT3 pathway related protein expression in liver were detected to study the role and mechanism of IL-22 and IL-22 BP in liver IRI.Results Compared with short-term ischemia-reperfusion injury group, mice in middle and long-term ischemia- reperfusion injury groups showed more severe liver injury.The concentration of serum IL-22 significantly increased but the activation of STAT3 pathway was significantly inhibited in long-term ischernia-reperfusion group.The ratio of IL-22BP / IL-22R a 1 niRNA increased significantly with the prolongation of ischemia time.Liver injury was significantly alleviated and the activation of STAT3 pathway was markedly up-regulated after the administration of exogenous recombinant 1L-22 in mice with long-term ischemia-reperfusion injury.Conclusions IL-22 can protect liver from ischemia-reperfusion injur)'; however, IL-22BP / IL-22R a 1 mRNA ratio is a negative indicator of liver injury, and the mechanism may be related to the regulation of STAT3 pathway activation by IL-22 / il-22bp axis dur-ing liver IRI.

Expression and Significance of IL-22BP in Intestinal Mucosa of Patients With Active Inflammatory Bowel Disease / 胃肠病学

Background:As the endogenous inhibitor of interleukin(IL)-22,IL-22 binding protein(IL-22BP)inhibits the protective effect of IL-22. Expression and significance of IL-22BP in intestinal mucosa of patients with active inflammatory bowel disease(IBD)remain unclear. Aims:To investigate the expression and significance of IL-22BP in intestinal mucosa of patients with active IBD. Methods:A total of 25 Crohn's disease(CD)and 36 ulcerative colitis(UC)patients from Jan. 2017 to Jan. 2018 at Shanghai General Hospital,Shanghai Jiao Tong University School of Medicine were enrolled, and 30 colonic polyp patients were served as controls. The disease activity of CD and UC was assessed. Expressions of IL-22BP mRNA and protein in intestinal mucosa were determined by real-time fluorescent quantitative PCR and immunohistochemistry,respectively. Correlation of IL-22BP protein expression with the disease activity of CD,UC was analyzed. Results:Compared with corresponding control group,expressions of IL-22BP mRNA in intestinal mucosa in CD and UC groups were significantly increased(CD:3.59 ± 0.83 vs. 1.08 ± 0.45,P<0.001;UC:2.19 ± 0.52 vs. 1.05 ± 0.34,P<0.001),and expressions of IL-22BP protein were also significantly increased(CD:6.12 ± 2.30 vs. 1.83 ± 1.86,P<0.001;UC:5.58 ± 2.27 vs. 2.23 ± 1.77,P<0.001). Expression of IL-22BP protein in intestinal mucosa was positively correlated with disease activity of CD(r =0. 649,P <0. 001)and UC(r =0. 732,P <0.001). Conclusions:Expressions of IL-22BP mRNA and protein are increased in intestinal mucosa of patients with active IBD, and the expression of IL-22BP protein is positively correlated with disease activity of IBD.