Interleukin-22 (IL-22), a cytokine from the IL-10 family produced by T cells and innate lymphoid cells, plays a crucial role in immune responses and tissue regeneration. Its association with liver disease has garnered significant attention; however, its exact impact remains controversial. This review aims to enhance the current understanding of the dual role of IL-22 in liver disease by exploring its protective and pathogenic effects. First, we provide an overview of IL-22 biology, including its source, receptors, and signaling pathways. Subsequently, we offer a comprehensive overview of the dual function of IL-22 in non-neoplastic liver disease, emphasizing its antiapoptotic and regenerative properties. We also discuss the applicability of the conclusions drawn from studies on nonalcoholic fatty liver disease to metabolic dysfunction-associated steatotic liver disease. Furthermore, we elaborate on the intricate role of IL-22 in hepatocellular carcinoma, particularly its influence on the tumor microenvironment, proliferation, and immune evasion. In conclusion, IL-22 is paradoxical in liver disease, acting as a friend and foe. It is imperative to understand this paradox to develop targeted therapies that capitalize on the beneficial effects of IL-22 while mitigating its detrimental effects.

Endometrial carcinoma (EC) is one of the most common gynecological malignant tumors, but its underlying pathogenic mechanisms are largely obscure. Interleukin-22 (IL-22), one cytokine in the tumor immune microenvironment, was reported to be associated with carcinoma progression. Here, we aimed to investigate the regulation of IL-22 in endometrial carcinoma. Enzyme-linked immunosorbent assay (ELISA) analysis of IL-22 was done in 27 controls and 51 patients with EC. We examined the proliferative potential, cycle progression, and signaling pathways modulated by IL-22 in EC cells. Western blot analysis was performed to investigate the expression of proliferative and cycle-related proteins in EC cells. The effect of IL-22 mediated by interleukin-22 receptor alpha 1 (IL-22RA1) was examined using cell transfection with small interfering RNA (siRNA). In addition, a xenograft tumor model was performed to assess the effect of IL-22 in vivo. We demonstrated significant up-regulation of serum IL-22 concentrations in EC patients (42.59 ± 23.72 pg/mL) compared to the control group (27.47 ± 8.29 pg/mL). High levels of IL-22 concentrations appear to correlate with malignant clinicopathological features of EC. Treatment with IL-22 promoted cell proliferation and G1/S phase progression in Ishikawa and HEC-1B cells. Western blot analysis revealed that c-Myc, cyclin E1, cyclin-dependent kinase (CDK)2, cyclin D1, CDK4, CDK6, p-extracellular signal-regulated kinase1/2 (p-ERK1/2), and p-p38 were highly expressed in EC cells exposed to IL-22. Moreover, in the EC mice model, we found that giving exogenous IL-22 increased tumor volume and weight. Immunohistochemistry showed that intra-tumor Ki-67 expression was up-regulated upon IL-22 treatment. The IL-22-mediated changes in cell proliferation, cycle progression, and protein expression can be effectively inhibited by the ERK1/2 inhibitor U0126 and the p38 inhibitor SB202190. In addition, the role of IL-22 in EC is receptor-dependent. Our findings suggest that IL-22 promotes endometrial carcinoma cell proliferation and G1/S phase progression by activating ERK1/2 and p38 signaling. Therefore, IL-22 may represent a potential therapeutic target for the treatment of endometrial carcinoma.

The intestinal epithelium of human infants is developmentally immature compared to that of adults. Exactly how this immaturity affects key epithelial functions and their interactions with nearby immune cells remains an understudied area of research, partly due to limited access to non-diseased infant gut tissues. Human intestinal organoids, or "mini guts" generated from tissue stem cells, are promising models for investigating intestinal biology and disease mechanisms. These three-dimensional structures closely mimic their tissue of origin, including cellular physiology and genetics. We have also previously shown that neonatal Th17 cells represent a distinct cell population with a cytokine profile skewed toward IL-22 production rather than IL-17A, as seen in adult Th17 cells.

In this study, we sought to model the impact of neonatal-derived Th17 cytokine, namely IL-22 and the intestinal epithelium using infant-derived ileal enteroids. We generated enteroids from ileal biopsies from infants (< 6 months old) and cultured them for seven days with standard organoid growth media, organoid media supplemented with conditioned media from cord-blood-derived Th17 cells, or media supplemented with recombinant IL-22. We assessed morphological changes and conducted transcriptomics profiling via RNAseq.

Exposing enteroids to neonatal Th17-cells-derived conditioned media led to enhanced growth, maturation, and differentiation as compared to control media. These effects were ablated when an IL-22 neutralizing antibody was used, while conversely, supplementing with recombinant IL-22 mimicked the Th17 effects, increasing intestinal epithelial cell proliferation and inducing marked differentiation of secretory cells. Our transcriptomic profiling similarly demonstrated significant changes in response to IL-22 with downregulation of Wnt and Notch signaling and upregulation of immune pathways, particularly interferon signaling. The transcriptomic data also suggested that IL-22 treatment led to changes in cell type composition with an increase in stem- and progenitor cells at the expense of enterocytes.

Taken together, our data suggests that early-life intestinal development is likely influenced by IL-22-dependent crosstalk between the infant epithelium and exposure to neighboring Th17 cells. This promotes epithelial cell maturation and immune readiness, reflected at both the morphological and molecular levels. Our work also provides a relevant framework for studying healthy infant gut development, which can be further leveraged to examine early-life gastrointestinal disorders, model complex human disease, and therapeutic testing while reducing reliance on animal models.

Acute liver failure (ALF) is a life-threatening medical condition, characterized by rapidly progressive hepatic dysfunction, coagulopathy and hepatic encephalopathy in patients without chronic liver disease, while acute-on-chronic liver failure (ACLF) occurs in patients with existing chronic liver disease. ALF and ACLF are often associated with multiple organ failure and a high short-term mortality. In this review, we briefly discuss the causes and pathogenesis of ALF and ACLF, the current options available for the treatment of both deadly maladies and interleukin-22 (IL-22), a novel promising drug that may have great therapeutic potential for ALF and ACLF treatment. IL-22 is a cytokine produced by immune cells but mainly targets epithelial cells including hepatocytes. IL-22 has been shown to protect against organ damage and reduce bacterial infection in many preclinical models and several clinical trials including alcohol-associated hepatitis. The potential application of IL-22 for the treatment of ALF and ACLF is also elaborated.

Psoriasis is an immune-mediated inflammatory skin disease. IL-22, a proinflammatory cytokine, is implicated in psoriasis pathogenesis; however, there is currently no established biological treatment targeting IL-22 or its receptor, IL-22Rα. Alloferon is a short peptide that has an antiinflammatory effect on skin disorders; however, little is known about its anti-inflammatory activity in psoriasis. We investigated the regulatory role of alloferon in the development of psoriasis in an imiquimod (IMQ)-induced psoriasis model through the regulation of IL-22Rα expression. The expression of IL-22Rα was analyzed by immunofluorescence staining in primary human keratinocytes. The effect of alloferon on the development of psoriasis was investigated in IMQ-induced wild-type and IL-22Rα KO mice. We found that alloferon decreased the expression of IL-22Rα in psoriasis-like keratinocytes treated with TNF-α, while epidermal hyperplasia was observed in IMQ-induced wild-type and IL-22Rα KO mice. In addition, the expression of IL-1β, IL-19, and IL-33 was suppressed when IL-22Rα KO mice were treated with alloferon. The findings of this study indicate that alloferon could be an effective potential drug for the treatment of psoriasis by interrupting IL-22 signaling and factors related to skin inflammation.

We present a patient with isolated autoimmune anterior scleritis and a patient with nonspecific orbital inflammation (NSOI). Both patients were treated with systemic corticosteroids during multiple recurrences, with the addition of various disease-modifying antirheumatic drugs (DMARDs), including biologics, in the case of scleritis, resulting in complications and local adverse events. Both patients were subsequently effectively managed using Janus kinase inhibitors (JAK-i), specifically baricitinib and tofacitinib without relapses of inflammation during the follow-up of more than one year. Only a slight transient increase in liver enzymes was reported in a patient with scleritis and no serious side effects.

Defense of the human body against damaging and pathogenic insults is a heavily regulated affair. A primary mechanism of defense at sites of insult are soluble mediators whose defensive maneuvers increase barrier integrity and promote pro-reparative and resolution processes. IL-22 is a cytokine in the IL-10 cytokine family that has garnered increased attention in recent years due to its intimate link in promoting resolution of inflammatory insults, while simultaneously being over expressed in certain fibrotic and chronic inflammatory-skewed diseases. The spatial action of IL-22 centers around the barrier sites of the body, including the skin, lungs, and gut mucosa. As such, a detailed understanding of the role of this cytokine, the producers and responders, and the diseases resulting from over- or under-expression have prominent impacts on a variety of disease outcomes. Herein we present a comprehensive review of IL-22; from historical perspectives and initial discovery, as well as more recent data that dramatically expands on the cellular sources and impact of this cytokine. We aim to showcase the duality of IL-22 and highlight addressable gaps in the field of IL-22 crosstalk and impacts at the ever-important mucosal and tissue barrier sites.

Primarily perceived as an anti-inflammatory and antimicrobial mediator in mucosa and skin, interleukin-22 (IL-22) has emerged as a pivotal metabolic regulator. Central to IL-22 signaling is its receptor, IL-22RA1. Through IL-22RA1, IL-22 orchestrates glucose homeostasis by modulating insulin secretion, reducing cellular stress in pancreatic islets, promoting beta-cell regeneration, and influencing hepatic glucose and lipid metabolism. These actions suggest its potential as a therapeutic for metabolic dysfunctions like diabetes, obesity, and steatohepatitis. However, clinical applications of IL-22 face challenges related to off-target effects and safety concerns. This review explores IL-22's physiological roles, regulatory mechanisms, and profound influence on metabolic tissues. It also underscores IL-22's dual role in metabolic health and disease, advocating further research to harness its therapeutic potential.

Interleukin-22 (IL-22) is a vital cytokine that is dysregulated in various autoimmune conditions including rheumatoid arthritis (RA), multiple sclerosis (MS), and Alzheimer's disease (AD). As the starting point for the activation of numerous signaling pathways, IL-22 plays an important role in the initiation and development of autoimmune diseases. Specifically, imbalances in IL-22 signaling can interfere with other signaling pathways, causing cross-regulation of target genes which ultimately leads to the development of immune disorders. This review delineates the various connections between the IL-22 signaling pathway and autoimmune disease, focusing on the latest understanding of the cellular sources of IL-22 and its effects on various cell types. We further explore progress with pharmacological interventions related to targeting IL-22, describing how such therapeutic strategies promise to usher in a new era in the treatment of autoimmune disease.

Systemic lupus erythematosus (SLE) is a complex autoimmune disease, characterized by considerable changes in peripheral lymphocyte structure and function, that plays a critical role in commencing and reviving the inflammatory and immune signaling pathways. In healthy individuals, B lymphocytes have a major role in guiding and directing defense mechanisms against pathogens. Certain changes in B lymphocyte phenotype, including alterations in surface and endosomal receptors, occur in the presence of SLE and lead to dysregulation of peripheral B lymphocyte subpopulations. Functional changes are characterized by loss of self-tolerance, intra- and extrafollicular activation, and increased cytokine and autoantibody production. T lymphocytes seem to have a supporting, rather than a leading, role in the disease pathogenesis. Substantial aberrations in peripheral T lymphocyte subsets are evident, and include a reduction of cytotoxic, regulatory, and advanced differentiated subtypes, together with an increase of activated and autoreactive forms and abnormalities in follicular T cells. Up-regulated subpopulations, such as central and effector memory T cells, produce pre-inflammatory cytokines, activate B lymphocytes, and stimulate cell signaling pathways. This review explores the pivotal roles of B and T lymphocytes in the pathogenesis of SLE and Lupus Nephritis, emphasizing the multifaceted mechanisms and interactions and their phenotypic and functional dysregulations.

Lung cancer, one of the most prevalent cancers worldwide, stands as the primary cause of cancer-related deaths. As is well-known, the utmost crucial risk factor contributing to lung cancer is smoking. In recent years, remarkable progress has been made in treating lung cancer, particularly non-small cell lung cancer (NSCLC). Nevertheless, the absence of effective and accurate biomarkers for diagnosing and treating lung cancer remains a pressing issue. Interleukin 22 (IL-22) is a member of the IL-10 cytokine family. It exerts biological functions (including induction of proliferation and anti-apoptotic signaling pathways, enhancement of tissue regeneration and immunity defense) by binding to heterodimeric receptors containing type 1 receptor chain (R1) and type 2 receptor chain (R2). IL-22 has been identified as a pro-cancer factor since dysregulation of the IL-22-IL-22R system has been implicated in the development of different cancers, including lung, breast, gastric, pancreatic, and colon cancers. In this review, we discuss the differential expression, regulatory role, and potential clinical significance of IL-22 in lung cancer, while shedding light on innovative approaches for the future.

Interleukin-22, discovered in the year of 2000, is a pleiotropic Th17 cytokine from the IL-10 family of cytokines. IL-22 signals through the type 2 cytokine receptor complex IL-22R and predominantly activates STAT3. This pathway leads to the transcription of several different types of genes, giving IL-22 context-specific functions ranging from inducing antimicrobial peptide expression to target cell proliferation. In recent years, it has been shown that IL-22 is involved in the pathogenesis of neoplasia in some cancers through its pro-proliferative and anti-apoptotic effects. This review highlights studies with recent discoveries and conclusions drawn on IL-22 and its involvement and function in various cancers. Such a study may be helpful to better understand the role of IL-22 in cancer so that new treatment could be developed targeting IL-22.

Germline gain-of-function (GOF) variants in STAT3 cause an inborn error of immunity associated with early-onset poly-autoimmunity and immune dysregulation. To study tissue-specific immune dysregulation, we used a mouse model carrying a missense variant (p.G421R) that causes human disease. We observed spontaneous and imiquimod (IMQ)-induced skin inflammation associated with cell-intrinsic local Th17 responses in STAT3 GOF mice. CD4+ T cells were sufficient to drive skin inflammation and showed increased Il22 expression in expanded clones. Certain aspects of disease, including increased epidermal thickness, also required the presence of STAT3 GOF in epithelial cells. Treatment with a JAK inhibitor improved skin disease without affecting local Th17 recruitment and cytokine production. These findings collectively support the involvement of Th17 responses in the development of organ-specific immune dysregulation in STAT3 GOF and suggest that the presence of STAT3 GOF in tissues is important for disease and can be targeted with JAK inhibition.

Metabolic dysfunction-associated steatotic liver disease (MASLD) comprises a spectrum of liver diseases that span simple steatosis, metabolic dysfunction-associated steatohepatitis (MASH) and fibrosis and may progress to cirrhosis and cancer. The pathogenesis of MASLD is multifactorial and is driven by environmental, genetic, metabolic and immune factors. This review will focus on the role of the type 3 cytokines IL-17 and IL-22 in MASLD pathogenesis and progression. IL-17 and IL-22 are produced by similar adaptive and innate immune cells such as Th17 and innate lymphoid cells, respectively. IL-17-related signaling is upregulated during MASLD resulting in increased chemokines and proinflammatory cytokines in the liver microenvironment, enhanced recruitment of myeloid cells and T cells leading to exacerbation of inflammation and liver disease progression. IL-17 may also act directly by activating hepatic stellate cells resulting in increased fibrosis. In contrast, IL-22 is a pleiotropic cytokine with a dominantly protective signature in MASLD and is currently being tested as a therapeutic strategy. IL-22 also exhibits beneficial metabolic effects and abrogates MASH-related inflammation and fibrosis development via inducing the production of anti-oxidants and anti-apoptotic factors. A sex-dependent effect has been attributed to both cytokines, most importantly to IL-22 in MASLD or related conditions. Altogether, IL-17 and IL-22 are key effectors in MASLD pathogenesis and progression. We will review the role of these two cytokines and cells that produce them in the development of MASLD, their interaction with host factors driving MASLD including sexual dimorphism, and their potential therapeutic benefits.

Microtubule-associated serine-threonine kinase-like (MASTL) has recently been identified as an oncogenic kinase given its overexpression in numerous cancers. Our group has shown that MASTL expression is upregulated in mouse models of sporadic colorectal cancer and colitis-associated cancer (CAC). CAC is one of the most severe complications of chronic inflammatory bowel disease (IBD), but a limited understanding of the mechanisms governing the switch from normal healing to neoplasia in IBD underscores the need for increased research in this area. However, MASTL levels in patients with IBD and its molecular regulation in IBD and CAC have not been studied. This study reveals that MASTL is upregulated by the cytokine interleukin (IL)-22, which promotes proliferation and has important functions in colitis recovery; however, IL-22 can also promote tumorigenesis when chronically elevated. Upon reviewing the publicly available data, we found significantly elevated MASTL and IL-22 levels in the biopsies from patients with late-stage ulcerative colitis compared with controls, and that MASTL upregulation was associated with high IL-22 expression. Our subsequent in vitro studies found that IL-22 increases MASTL expression in intestinal epithelial cell lines, which facilitates IL-22-mediated cell proliferation and downstream survival signaling. Inhibition of AKT activation abrogated IL-22-induced MASTL upregulation. We further found an increased association of carbonic anhydrase IX (CAIX) with MASTL in IL-22-treated cells, which stabilized MASTL expression. Inhibition of CAIX prevented IL-22-induced MASTL expression and cell survival. Overall, we show that IL-22/AKT signaling increases MASTL expression to promote cell survival and proliferation. Furthermore, CAIX associates with and stabilizes MASTL in response to IL-22 stimulation.NEW & NOTEWORTHY MASTL is upregulated in colorectal cancer; however, its role in colitis and colitis-associated cancer is poorly understood. This study is the first to draw a link between MASTL and IL-22, a proinflammatory/intestinal epithelial recovery-promoting cytokine that is also implicated in colon tumorigenesis. We propose that IL-22 increases MASTL protein stability by promoting its association with CAIX potentially via AKT signaling to promote cell survival and proliferation.

Interleukin (IL)-22 is a potential therapeutic protein for the treatment of metabolic diseases such as obesity, type 2 diabetes, and metabolic dysfunction-associated steatotic liver disease due to its involvement in multiple cellular pathways and observed hepatoprotective effects. The short serum half-life of IL-22 has previously limited its use in clinical applications; however, the development of mRNA-lipid nanoparticle (LNP) technology offers a novel therapeutic approach that uses a host-generated IL-22 fusion protein. In the present study, the effects of administration of an mRNA-LNP encoding IL-22 on metabolic disease parameters was investigated in various mouse models.

C57BL/6NCrl mice were used to confirm mouse serum albumin (MSA)-IL-22 protein expression prior to assessments in C57BL/6NTac and CETP/ApoB transgenic mouse models of metabolic disease. Mice were fed either regular chow or a modified amylin liver nonalcoholic steatohepatitis-inducing diet prior to receiving either LNP-encapsulated MSA-IL-22 or MSA mRNA via intravenous or intramuscular injection. Metabolic markers were monitored for the duration of the experiments, and postmortem histology assessment and analysis of metabolic gene expression pathways were performed.

MSA-IL-22 was detectable for ≥8 days following administration. Improvements in body weight, lipid metabolism, glucose metabolism, and lipogenic and fibrotic marker gene expression in the liver were observed in the MSA-IL-22-treated mice, and these effects were shown to be durable.

These results support the application of mRNA-encoded IL-22 as a promising treatment strategy for metabolic syndrome and associated comorbidities in human populations.

Ubiquitin-specific proteases (USPs), a large subset of more than 50 deubiquitinase proteins, have recently emerged as promising targets in cancer. However, their role in immune cell regulation, particularly in T cell activation, differentiation, and effector functions, remains largely unexplored.

We utilized a USP28 knockout mouse line to study the effect of USP28 on T cell activation and function, and its role in intestinal inflammation using the dextran sulfate sodium (DSS)-induced colitis model and a series of in vitro assays.

Our results show that USP28 exerts protective effects in acute intestinal inflammation. Mechanistically, USP28 knockout mice (USP28-/-) exhibited an increase in total T cells mainly due to an increased CD8+ T cell content. Additionally, USP28 deficiency resulted in early defects in T cell activation and functional changes. Specifically, we observed a reduced expression of IL17 and an increase in inducible regulatory T (iTreg) suppressive functions. Importantly, activated T cells lacking USP28 showed increased STAT5 phosphorylation. Consistent with these findings, these mice exhibited increased susceptibility to acute DSS-induced intestinal inflammation, accompanied by elevated IL22 cytokine levels.

Our findings demonstrate that USP28 is essential for T cell functionality and protects mice from acute DSS-induced colitis by regulating STAT5 signaling and IL22 production. As a T cell regulator, USP28 plays a crucial role in immune responses and intestinal health.

Prurigo nodularis (PN) and chronic pruritus of unknown origin (CPUO) are chronic pruritic diseases that dramatically impair quality of life, but therapeutic options are limited. Abrocitinib, a Janus kinase 1 inhibitor, represents a promising therapy for both conditions.

To assess the efficacy and safety of 200-mg oral abrocitinib administered once daily in adults with moderate to severe PN or CPUO.

This phase 2, open-label, nonrandomized controlled trial conducted between September 2021 and July 2022 took place at a single center in the US. A total of 25 adult patients with moderate to severe PN or CPUO were screened. Ten patients with PN and 10 patients with CPUO were enrolled. All 20 patients completed the 12-week treatment period, 18 of whom completed the 4-week follow-up period.

Abrocitinib, 200 mg, by mouth once daily for 12 weeks.

The primary efficacy end point was the percent change in weekly Peak Pruritus Numerical Rating Scale (PP-NRS) scores from baseline to week 12. Key secondary end points included the percentage of patients achieving at least a 4-point reduction in weekly PP-NRS score from baseline to week 12 and the percent change in Dermatology Life Quality Index (DLQI) scores.

A total of 10 patients with PN (mean [SD] age, 58.6 [13.1] years; all were female) and 10 patients with CPUO (mean [SD] age, 70.7 [5.6] years; 2 were female) enrolled in the study. The mean (SD) baseline PP-NRS score was 9.2 (1.0) for PN and 8.2 (1.2) for CPUO. PP-NRS scores decreased by 78.3% in PN (95% CI, -118.5 to -38.1; P < .001) and 53.7% in CPUO (95% CI, -98.8 to -8.6; P = .01) by week 12. From baseline to week 12, 8 of 10 patients with PN and 6 of 10 patients with CPUO achieved at least a 4-point improvement on the PP-NRS. Both groups experienced significant improvement in quality of life as demonstrated by percent change in DLQI scores (PN: -53.2% [95% CI, -75.3% to -31.1%]; P = .002; CPUO: -49.0% [95% CI, -89.6% to -8.0%]; P = .02). The most common adverse event among patients was acneiform eruption in 2 of 20 patients (10%). No serious adverse events occurred.

The results of this nonrandomized controlled trial suggest that abrocitinib monotherapy may be effective and tolerated well in adults with PN or CPUO. Randomized, double-blind, placebo-controlled trials are warranted to validate these findings.

ClinicalTrials.gov Identifier: NCT05038982.

In mammals, IL-22 is considered as a critical cytokine regulating of immunity and homeostasis at barrier surfaces. Although IL-22 have been functional characterization in different species of fish, the studies about distinct responses of IL-22 in different organs/tissues/cell types is rather limited. Here, we identified and cloned IL-22 gene (named as Ec-IL-22) from grouper (Epinephelus coioides). Ec-IL-22 gene was detected in all orangs/tissues examined, and was induced in intestine, gill, spleen, head kidney, and primary head kidney/intestine leukocytes following the stimulation of LPS and poly (I:C), as well as Vibrio harveyi and Singapore grouper iridovirus infection (SGIV). In addition, the stimulation of DSS could induce the expression of Ec-IL-22 in intestine and primary leukocytes from intestine. Importantly, the treatment of recombinant Ec-IL-22 induced the mRNA level of proinflammatory cytokines in primary intestine/head kidney leukocytes. The present results improve the understanding of expression patterns and functional characteristics of fish IL-22 in different organs/tissues/cell types.

Cytokines play a crucial role in the structure and function of blood vessels in hypertension. Hypertension damages blood vessels by mechanisms linked to shear forces, activation of the renin-angiotensin-aldosterone and sympathetic nervous systems, oxidative stress, and a proinflammatory milieu that lead to the generation of neoantigens and damage-associated molecular patterns, ultimately triggering the release of numerous cytokines. Damage-associated molecular patterns are recognized by PRRs (pattern recognition receptors) and activate inflammatory mechanisms in endothelial cells, smooth muscle cells, perivascular nerves, and perivascular adipose tissue. Activated vascular cells also release cytokines and express factors that attract macrophages, dendritic cells, and lymphocytes to the blood vessels. Activated and differentiated T cells into Th1, Th17, and Th22 in secondary lymphoid organs migrate to the vessels, releasing specific cytokines that further contribute to vascular dysfunction and remodeling. This chronic inflammation alters the profile of endothelial and smooth muscle cells, making them dysfunctional. Here, we provide an overview of how cytokines contribute to hypertension by impacting the vasculature. Furthermore, we explore clinical perspectives about the modulation of cytokines as a potential therapeutic intervention to specifically target hypertension-linked vascular dysfunction.

Anxiety is a prevalent mental illness known for its high incidence, comorbidity, and tendency to recur, posing significant societal and individual burdens. Studies have highlighted Interleukin-19 (IL-19) as having potential relevance in neuropsychiatric disorders. Our previous research revealed that IL-19 overexpression in colonies exacerbated anxiety-related behaviors induced by dextran sodium sulfate/stress. However, the precise role and molecular mechanisms of IL-19 in anxiety regulation remain uncertain. In this study, we initiated an acute restraint stress (ARS)-induced anxious mouse model and identified heightened expression of IL-19 and IL-20Rα in the medial prefrontal cortex (mPFC) of ARS mice. Notably, IL-19 and IL-20Rα were predominantly present in the excitatory pyramidal neurons of the mPFC under both basal and ARS conditions. Utilizing the adeno-associated virus (AAV) strategy, we demonstrated that IL-19 overexpression in the mPFC induced anxiety-related behaviors and elevated stress susceptibility. Additionally, we observed decreased protein levels of brain-derived neurotrophic factor (BDNF) and postsynaptic density protein 95 (PSD95) in the mPFC of IL-19 overexpression mice, accompanied by reduced phosphorylation of in the p38, JNK, and Erk signaling pathways. These findings emphasize the role of IL-19 in modulating anxiety-related behaviors within the mPFC and suggest its potential as a pathological gene and therapeutic target for anxiety.

Multiple sclerosis (MS) is a central nervous system (CNS) demyelinating autoimmune disease with increasing global prevalence. It predominantly affects females, especially those of European descent. The interplay between environmental factors and genetic predisposition plays a crucial role in MS etiopathogenesis.

We searched recent relevant literature on reputable databases, which include, PubMed, Embase, Web of Science, Scopus, and ScienceDirect using the following keywords: multiple sclerosis, pathogenesis, autoimmunity, demyelination, therapy, and immunotherapy.

Various animal models have been employed to investigate the MS etiopathogenesis and therapeutics. Autoreactive T cells within the CNS recruit myeloid cells through chemokine expression, leading to the secretion of inflammatory cytokines driving the MS pathogenesis, resulting in demyelination, gliosis, and axonal loss. Key players include T cell lymphocytes (CD4+ and CD8+), B cells, and neutrophils. Signaling dysregulation in inflammatory pathways and the immunogenetic basis of MS are essential considerations for any successful therapy to MS. Data indicates that B cells and neutrophils also have significant roles in MS, despite the common belief that T cells are essential. High neutrophil-to-lymphocyte ratios correlate with MS severity, indicating their contribution to disease progression. Dysregulated signaling pathways further exacerbate MS progression.

MS remains incurable, but disease-modifying therapies, monoclonal antibodies, and immunomodulatory drugs offer hope for patients. Research on the immunogenetics and immunoregulatory functions of gut microbiota is continuing to provide light on possible treatment avenues. Understanding the complex interplay between genetic predisposition, environmental factors, and immune dysregulation is critical for developing effective treatments for MS.

Severe acute pancreatitis (SAP) begins with premature activation of enzymes, promoted by the immune system, triggering a potential systemic inflammatory response that leads to organ failure with increased mortality and a bleak prognosis. Interleukin-22 (IL-22) is a cytokine that may have a significant role in SAP. IL-22, a member of the IL-10 cytokine family, has garnered growing interest owing to its potential tissue-protective properties. Recently, emerging research has revealed its specific effects on pancreatic diseases, particularly SAP. This paper provides a review of the latest knowledge on the role of IL-22 and its viability as a therapeutic target in SAP.

Interleukin 22 (IL-22) promotes intestinal barrier integrity, stimulating epithelial cells to enact defense mechanisms against enteric infections, including the production of antimicrobial peptides. IL-22 binding protein (IL-22BP) is a soluble decoy encoded by the Il22ra2 gene that decreases IL-22 bioavailability, attenuating IL-22 signaling. The impact of IL-22BP on gut microbiota composition and functioning is poorly understood. We found that Il22ra2-/- mice are better protected against Clostridioides difficile and Citrobacter rodentium infections. This protection relied on IL-22-induced antimicrobial mechanisms before the infection occurred, rather than during the infection itself. Indeed, the gut microbiota of Il22ra2-/- mice mitigated infection of wild-type (WT) mice when transferred via cohousing or by cecal microbiota transplantation. Indicator species analysis of WT and Il22ra2-/- mice with and without cohousing disclosed that IL22BP deficiency yields a gut bacterial composition distinct from that of WT mice. Manipulation of dietary fiber content, measurements of intestinal short-chain fatty acids and oral treatment with acetate disclosed that resistance to C. difficile infection is related to increased production of acetate by Il22ra2-/--associated microbiota. Together, these findings suggest that IL-22BP represents a potential therapeutic target for those at risk for or with already manifest infection with this and perhaps other enteropathogens.

Idiopathic pulmonary fibrosis (IPF) is one of the most fatal chronic interstitial lung diseases with unknown pathogenesis, current treatments cannot truly reverse the progression of the disease. Pulmonary macrophages, especially bone marrow derived pro-fibrotic macrophages, secrete multiple kinds of profibrotic mediators (SPP1, CD206, CD163, IL-10, CCL18…), thus further promote myofibroblast activation and fibrosis procession. IL20Rb is a cell-surface receptor that belongs to IL-20 family. The role of IL20Rb in macrophage activation and pulmonary fibrosis remains unclear. In this study, we established a bleomycin-induced pulmonary fibrosis model, used IL4/13-inducing THP1 cells to induce profibrotic macrophage (M2-like phenotype) polarization models. We found that IL20Rb is upregulated in the progression of pulmonary fibrosis, and its absence can alleviate the progression of pulmonary fibrosis. In addition, we demonstrated that IL20Rb promote the activation of bone marrow derived profibrotic macrophages by regulating the Jak2/Stat3 and Pi3k/Akt signaling pathways. In terms of therapeutic strategy, we used IL20Rb neutralizing antibodies for animal administration, which was found to alleviate the progression of IPF. Our results suggest that IL20Rb plays a profibrotic role by promoting profibrotic macrophage polarization, and IL20Rb may become a potential therapeutic target for IPF. Neutralizing antibodies against IL20Rb may become a potential drug for the clinical treatment of IPF.

Acute pancreatitis (AP) is one of the most common acute abdominal disorders; due to the lack of specific treatment, the treatment of acute pancreatitis, especially serious acute pancreatitis (SAP), is difficult and challenging. We will observe the changes of Interleukin -22 levels in acute pancreatitis animal models, and explore the mechanism of Interleukin -22 in acute pancreatitis.

This study aims to assess the potential protective effect of Interleukin -22 on caerulein-induced acute pancreatitis and to explore its mechanism.

Blood levels of amylase and lipase and Interleukin -22 were assessed in mice with acute pancreatitis. In animal model and cell model of caerulein-induced acute pancreatitis, the mRNA levels of P62 and Beclin-1 were determined using PCR, and the protein expression of P62, LC3-II, mTOR, AKT, p-mTOR, and p-AKT were evaluated through Western blot analysis.

Interleukin -22 administration reduced blood amylase and lipase levels and mitigated tissue damage in acute pancreatitis mice model. Interleukin -22 inhibited the relative mRNA levels of P62 and Beclin-1, and the Interleukin -22 group showed a decreased protein expression of LC3-II and P62 and the phosphorylation of the AKT/mTOR pathway. Furthermore, we obtained similar results in the cell model of acute pancreatitis.

This study suggests that Interleukin -22 administration could alleviate pancreatic damage in caerulein-induced acute pancreatitis. This effect may result from the activation of the AKT/mTOR pathway, leading to the inhibition of autophagy. Consequently, Interleukin -22 shows potential as a treatment.

Insufficient remnant liver volume (RLV) after the resection of hepatic malignancy could lead to liver failure and mortality. Portal vein ligation (PVL) prior to hepatectomy is subsequently introduced to increase the remnant liver volume and improve the outcome of hepatic malignancy. IL-22 has previously been reported to promote liver regeneration, while facilitating tumor development in the liver via Steap4 upregulation. Here we performed PVL in mouse models to study the role of IL-22 in liver regeneration post-PVL.

Liver weight and volume was measured via magnetic resonance imaging (MRI). Immunohistochemistry for Ki67 and hepatocyte growth factor (HGF) was performed. IL-22 was analyzed by flow cytometry and quantitative polymerase chain reaction (qPCR) was used for acquisition of Il-33, Steap4, Fga, Fgb and Cebpd. To analyze signaling pathways, mice with deletion of STAT3 and a neutralizing antibody for IL-22 were used.

The remnant liver weight and volume increased over time after PVL. Additionally, we found that liver regenerative molecules, including Ki67 and HGF, were significantly increased in remnant liver at day 3 post-PVL, as well as IL-22. Administration of IL-22 neutralizing antibody could reduce Ki67 expression after PVL. The upregulation of IL-22 after PVL was mainly derived from innate cells. IL-22 blockade resulted in lower levels of IL-33 and Steap4 in the remnant liver, which was also the case in mice with deletion of STAT3, the main downstream signaling molecule of IL-22, in hepatocytes.

IL-22 promotes liver regeneration after PVL. Thus, a combination of IL-22 supplementation and Steap4 blockade could potentially be applied as a novel therapeutic approach to boost liver regeneration without facilitating tumor progression after PVL.

Oncolytic viruses (OVs) are appealing anti-tumor agents. But it is limited in its effectiveness. In this study, we used combination therapy with immune checkpoint inhibitor to enhance the antitumor efficacy of OVs. Using reverse genetics technology, we rescued an oncolytic influenza virus with the name delNS1-GM-CSF from the virus. After identifying the hemagglutination and 50% tissue culture infectivedose (TCID50) of delNS1-GM-CSF, it was purified, and the viral morphology was observed under electron microscopy. Reverse transcription quantitative-polymerase chain reaction (RT-qPCR) was used to identify the level of GM-CSF expression in delNS1-GM-CSF, and the GM-CSF expression level was determined after infection with delNS1-GM-CSF by enzyme linked immunosorbent assay (ELISA). To study the tumor-killing effect of delNS1-GM-CSF, we utilized the hepatocellular carcinoma (HCC) tumor-bearing mouse model. To examine signaling pathways, we performed transcriptome sequencing on mouse tumor tissue and applied western blotting to confirm the results. Changes in T-cell infiltration in HCC tumors following treatment were analyzed using flow cytometry and immunohistochemistry. DelNS1-GM-CSF can target and kill HCCs without damaging normal hepatocytes. DelNS1-GM-CSF combined with programmed cell death 1 blockade therapy enhanced anti-tumor effects and significantly improved mouse survival. Further, we found that combination therapy had an antitumor impact via the janus kinase-signal transducer and activator of transcription (JAK2-STAT3) pathway as well as activated CD4+ and CD8+T cells. Interestingly, combined therapy also showed promising efficacy in distant tumors. DelNS1-GM-CSF is well targeted. Mechanistic investigation revealed that it functions through the JAK2-STAT3 pathway. Combination immunotherapies expected to be a novel strategy for HCC immunotherapy.

Chronic rhinosinusitis (CRS) is usually accompanied by mucin hypersecretion that can lead to mucus accumulation and impair nasal mucociliary clearance, thus exacerbating airway inflammation. Abnormal mucin hypersecretion is regulated by different T helper (Th) cytokines, which are associated with different endotype-driven inflammatory responses. Therefore, it is of great significance to understand how these factors regulate mucin hypersecretion to provide precise treatment strategies for different endotypes of CRS. BODY: Thus far, the most common endotypes of CRS are classified as type 1, type 2, or type 3 immune responses based on innate and adaptive cell-mediated effector immunity, and the representative Th cytokines in these immune responses, such as IFN-γ, TNF-α, IL-4, IL-5, IL-13, IL-10, IL-17, and IL-22, play an important regulatory role in mucin secretion. We reviewed all the related literature in the PubMed database to determine the expression of these Th cytokines in CRS and the role they play in the regulation of mucin secretion.

We believe that the main Th cytokines involved in specific endotypes of CRS play a key role in regulating abnormal mucin secretion, which contributes to better understanding of the pathogenesis of CRS and provides therapeutic targets for airway inflammatory diseases associated with mucin hypersecretion.

Although calcific aortic valve disease (CAVD) is a common valvular disease among elderly populations and its incidence has markedly increased in recent decades, the pathogenesis of CAVD remains unclear. In this study, we explored the potential role of interleukin (IL)-22 and the underlying molecular mechanism in CAVD.

Our results showed that IL-22 was upregulated in calcific aortic valves from CAVD patients, and its main sources were CD3+ T cells and CD68+ macrophages. Human aortic valve interstitial cells (VICs) expressed the IL-22-specific receptor IL-22R1, and IL-22R1 expression also was elevated in calcified valves. Treatment of cultured human VICs with recombinant human IL-22 resulted in markedly increased expression of osteogenic proteins Runt-related transcription factor 2 (RUNX2) and alkaline phosphatase (ALP), as well as increased matrix calcium deposition. Moreover, siRNA silencing of IL-22R1 blocked the pro-osteogenic effect of IL-22 in VICs. In IL-22-treated VICs, we also observed increased phosphorylation of JAK3 and STAT3 and nuclear translocation of STAT3. Pretreatment with a specific JAK3 inhibitor, WHIP-154, or siRNA knockout of STAT3 effectively mitigated the IL-22-induced osteoblastic trans-differentiation of human VICs.

Together, these data indicate that IL-22 promotes osteogenic differentiation of VICs by activating JAK3/STAT3 signaling. Based on our results demonstrating a pro-osteogenic role of IL-22 in human aortic valves, pharmacological inhibition of IL-22 signaling may represent a potential strategy for alleviating CAVD.

Since atopic dermatitis (AD) is a heterogeneous condition, the subtyping of AD is a crucial issue. The classical subtypes of AD are represented by extrinsic and intrinsic subtypes, European-American and Asian subtypes, and adult and pediatric subtypes. While the subtyping of AD was historically conducted based on the phenotype, recent findings on the mechanisms of AD have revealed the importance of the endotype, which can characterize individual patients more accurately. Considering the current development of AD therapies, AD endotyping is a prerequisite for a personalized therapeutic choice. Endotypes of AD can be stratified from different viewpoints, including cytokine expression patterns, allergen properties, epidermal barrier conditions, ceramide variation, the involvement of innate immunity, and serum biomarkers. Among them, the cytokine-based endotype seems to be the most useful one and is categorized into type 2 cytokine (IL-4, IL-13 and IL-31)-high, type 1 cytokine (IFN-γ)-high, and/or type 3 cytokine (IL-22 and IL-17)-high, or mixed subtypes. Recently proposed biomarker endotyping aims at individualized treatment options, although the daily clinical use of endotypes is a future issue. To better understand the endotypes for clinicians, attempts to adjust each of the classical subtypes to endotypes are required. This review will discuss the correspondence of the classical subtypes to the various endotypes that have recently been proposed.

Atopic dermatitis (AD) is a heterogeneous, chronic, relapsing, inflammatory skin disease associated with considerable physical, psychological, and economic burden. The pathology of AD includes complex interactions involving abnormalities in immune and skin barrier genes, skin barrier disruption, immune dysregulation, microbiome disturbance, and other environmental factors. Many of the cytokines involved in AD pathology, including IL-4, IL-13, IL-22, IL-31, thymic stromal lymphopoietin, and IFN-γ, signal through the Janus kinase (JAK)-signal transducer and activation of transcription (STAT) pathway. The JAK family includes JAK1, JAK2, JAK3, and tyrosine kinase 2; the STAT family includes STAT1, STAT2, STAT3, STAT4, STAT5A/B, and STAT6. Activation of the JAK-STAT pathway has been implicated in the pathology of several immune-mediated inflammatory diseases, including AD. However, the exact mechanisms of JAK-STAT involvement in AD have not been fully characterized. This review aims to discuss current knowledge about the role of the JAK-STAT signaling pathway and, specifically, the role of JAK1 in the pathology and symptomology of AD.

Interleukin 22 (IL-22) plays a role in inflammatory diseases. However, whether IL-22 affects the function of ovarian granulosa cells (GCs) and its relationship with Polycystic Ovary Syndrome (PCOS)remains unclear.

We investigated the level of IL-22 in human follicular fluid using ELISA. The expression and localization of the IL-22 receptor 1 (IL-22R1) in GCs were investigated by RT-PCR and immunofluorescence staining, respectively. The proliferation of KGN cells (human GCs line) was assessed by CCK-8 assay and EdU assay after treatment with recombinant human IL-22 (rhIL-22) and lipopolysaccharide (LPS). Apoptosis was assessed using flow cytometry. Apoptotic proteins and steroidogenic genes were detected by western blotting.

ELISA's results showed that compared with the control group, PCOS patients showed lower expression of IL-22 in follicular fluid. Immunofluorescence showed that IL-22R1 is expressed and localized in human granulosa cell membranes. IL-22 promoted cell proliferation and reversed LPS-induced inhibition of cell proliferation. IL-22 alone did not affect apoptotic or steroidogenic protein expression, however, it reversed LPS-induced apoptosis via downregulation of Bcl-2, upregulation of Bax and cleaved caspase-3, and restoration of LPS-downregulated StAR, CYP11A1, and CYP19A1 expression. Western blotting confirmed that IL-22 activated the JAK2/STAT3 signaling.

IL-22 promotes cell proliferation, inhibits apoptosis, and regulates KGN cell steroidogenesis confronted with LPS, and decreased IL-22 may be involved in the development of PCOS.