IL-37 requires the receptors IL-18Rα and IL-1R8 (SIGIRR) to carry out its multifaceted anti-inflammatory program upon innate signal transduction.

Interleukin 37 (IL-37) and IL-1R8 (SIGIRR or TIR8) are anti-inflammatory orphan members of the IL-1 ligand family and IL-1 receptor family, respectively. Here we demonstrate formation and function of the endogenous ligand-receptor complex IL-37-IL-1R8-IL-18Rα. The tripartite complex assembled rapidly on the surface of peripheral blood mononuclear cells upon stimulation with lipopolysaccharide. Silencing of IL-1R8 or IL-18Rα impaired the anti-inflammatory activity of IL-37. Whereas mice with transgenic expression of IL-37 (IL-37tg mice) with intact IL-1R8 were protected from endotoxemia, IL-1R8-deficient IL-37tg mice were not. Proteomic and transcriptomic investigations revealed that IL-37 used IL-1R8 to harness the anti-inflammatory properties of the signaling molecules Mer, PTEN, STAT3 and p62(dok) and to inhibit the kinases Fyn and TAK1 and the transcription factor NF-κB, as well as mitogen-activated protein kinases. Furthermore, IL-37-IL-1R8 exerted a pseudo-starvational effect on the metabolic checkpoint kinase mTOR. IL-37 thus bound to IL-18Rα and exploited IL-1R8 to activate a multifaceted intracellular anti-inflammatory program.

Genetic landscape of pediatric acute liver failure of indeterminate origin.

BACKGROUND AND AIMS: Pediatric acute liver failure (PALF) is a life-threatening condition. In Europe, the main causes are viral infections (12%-16%) and inherited metabolic diseases (14%-28%). Yet, in up to 50% of cases the underlying etiology remains elusive, challenging clinical management, including liver transplantation. We systematically studied indeterminate PALF cases referred for genetic evaluation by whole-exome sequencing (WES), and analyzed phenotypic and biochemical markers, and the diagnostic yield of WES in this condition. APPROACH AND RESULTS: With this international, multicenter observational study, patients (0-18 y) with indeterminate PALF were analyzed by WES. Data on the clinical and biochemical phenotype were retrieved and systematically analyzed. RESULTS: In total, 260 indeterminate PALF patients from 19 countries were recruited between 2011 and 2022, of whom 59 had recurrent PALF. WES established a genetic diagnosis in 37% of cases (97/260). Diagnostic yield was highest in children with PALF in the first year of life (41%), and in children with recurrent acute liver failure (64%). Thirty-six distinct disease genes were identified. Defects in NBAS (n=20), MPV17 (n=8), and DGUOK (n=7) were the most frequent findings. When categorizing, the most frequent were mitochondrial diseases (45%), disorders of vesicular trafficking (28%), and cytosolic aminoacyl-tRNA synthetase deficiencies (10%). One-third of patients had a fatal outcome. Fifty-six patients received liver transplantation. CONCLUSIONS: This study elucidates a large contribution of genetic causes in PALF of indeterminate origin with an increasing spectrum of disease entities. The high proportion of diagnosed cases and potential treatment implications argue for exome or in future rapid genome sequencing in PALF diagnostics.

Patient-derived organoid biobank identifies epigenetic dysregulation of intestinal epithelial MHC-I as a novel mechanism in severe Crohn's Disease.

OBJECTIVE: Epigenetic mechanisms, including DNA methylation (DNAm), have been proposed to play a key role in Crohn's disease (CD) pathogenesis. However, the specific cell types and pathways affected as well as their potential impact on disease phenotype and outcome remain unknown. We set out to investigate the role of intestinal epithelial DNAm in CD pathogenesis. DESIGN: We generated 312 intestinal epithelial organoids (IEOs) from mucosal biopsies of 168 patients with CD (n=72), UC (n=23) and healthy controls (n=73). We performed genome-wide molecular profiling including DNAm, bulk as well as single-cell RNA sequencing. Organoids were subjected to gene editing and the functional consequences of DNAm changes evaluated using an organoid-lymphocyte coculture and a nucleotide-binding oligomerisation domain, leucine-rich repeat and CARD domain containing 5 (NLRC5) dextran sulphate sodium (DSS) colitis knock-out mouse model. RESULTS: We identified highly stable, CD-associated loss of DNAm at major histocompatibility complex (MHC) class 1 loci including NLRC5 and cognate gene upregulation. Single-cell RNA sequencing of primary mucosal tissue and IEOs confirmed the role of NLRC5 as transcriptional transactivator in the intestinal epithelium. Increased mucosal MHC-I and NLRC5 expression in adult and paediatric patients with CD was validated in additional cohorts and the functional role of MHC-I highlighted by demonstrating a relative protection from DSS-mediated mucosal inflammation in NLRC5-deficient mice. MHC-I DNAm in IEOs showed a significant correlation with CD disease phenotype and outcomes. Application of machine learning approaches enabled the development of a disease prognostic epigenetic molecular signature. CONCLUSIONS: Our study has identified epigenetically regulated intestinal epithelial MHC-I as a novel mechanism in CD pathogenesis.

Acute kidney injury in lamotrigine-induced DRESS syndrome.

We present a case of lamotrigine-triggered DRESS (drug reaction with eosinophilia and systemic symptoms) syndrome with acute kidney injury stage 3. A 17-year-old girl with known epilepsy treated with lamotrigine presented with acute kidney injury as well as skin eruption, fever, and apathy. Extended diagnostics, considering infectious and autoimmune diseases, remained unremarkable. Lamotrigine blood levels were within the target range. Kidney biopsy showed acute interstitial nephritis with tubular necrosis. Methylprednisolone pulse therapy led to an improvement in kidney function; skin eruption and neurological symptoms resolved. During the hospital stay, the girl admitted to inconsistent and variable intake of lamotrigine, occasionally resulting in notable overdosing. This report demonstrates that acute kidney injury in lamotrigine-induced DRESS syndrome is an acute interstitial nephritis with tubular necrosis, an aspect that has not been deeply characterized so far. Additionally, we aim to elevate awareness towards non-adherence as cause of disease, especially among the adolescent population.

Biallelic known and novel DCDC2 variants in cholestatic liver disease: Phenotype-genotype observations in four children.

Neonatal sclerosing cholangitis (NSC) is associated with progressing biliary fibrosis that often requires liver transplantation in childhood. Several recent studies have identified variants in DCDC2, encoding doublecortin domain-containing protein 2 (DCDC2), expressed in primary cilia, that accompany syndromic disease and NSC. We report four patients with hepatobiliary disease associated with two novel homozygous or compound heterozygous variants in DCDC2. Three patients with protein-truncating variants in DCDC2, expressing no DCDC2, presented with the originally described severe hepatic phenotype in infancy. One patient with a novel homozygous DCDC2 missense variant shows a markedly milder phenotype only manifest in childhood and with retained DCDC2 expression. Concomitant nephronophthisis is present in three patients and learning disability in two. This report widens the phenotypic spectrum of DCDC2-associated hepatobiliary disease. Testing for DCDC2 expression and DCDC2 variants should be included in the evaluation of cholangiopathy of unknown aetiology in childhood as well as in infancy.

Inflammation in Children with CKD Linked to Gut Dysbiosis and Metabolite Imbalance.

BACKGROUND: CKD is characterized by a sustained proinflammatory response of the immune system, promoting hypertension and cardiovascular disease. The underlying mechanisms are incompletely understood but may be linked to gut dysbiosis. Dysbiosis has been described in adults with CKD; however, comorbidities limit CKD-specific conclusions. METHODS: We analyzed the fecal microbiome, metabolites, and immune phenotypes in 48 children (with normal kidney function, CKD stage G3-G4, G5 treated by hemodialysis [HD], or kidney transplantation) with a mean±SD age of 10.6±3.8 years. RESULTS: Serum TNF-α and sCD14 were stage-dependently elevated, indicating inflammation, gut barrier dysfunction, and endotoxemia. We observed compositional and functional alterations of the microbiome, including diminished production of short-chain fatty acids. Plasma metabolite analysis revealed a stage-dependent increase of tryptophan metabolites of bacterial origin. Serum from patients on HD activated the aryl hydrocarbon receptor and stimulated TNF-α production in monocytes, corresponding to a proinflammatory shift from classic to nonclassic and intermediate monocytes. Unsupervised analysis of T cells revealed a loss of mucosa-associated invariant T (MAIT) cells and regulatory T cell subtypes in patients on HD. CONCLUSIONS: Gut barrier dysfunction and microbial metabolite imbalance apparently mediate the proinflammatory immune phenotype, thereby driving the susceptibility to cardiovascular disease. The data highlight the importance of the microbiota-immune axis in CKD, irrespective of confounding comorbidities.

IL-37 is a fundamental inhibitor of innate immunity.

The function of interleukin 37 (IL-37; formerly IL-1 family member 7) has remained elusive. Expression of IL-37 in macrophages or epithelial cells almost completely suppressed production of pro-inflammatory cytokines, whereas the abundance of these cytokines increased with silencing of endogenous IL-37 in human blood cells. Anti-inflammatory cytokines were unaffected. Mice with transgenic expression of IL-37 were protected from lipopolysaccharide-induced shock, and showed markedly improved lung and kidney function and reduced liver damage after treatment with lipopolysaccharide. Transgenic mice had lower concentrations of circulating and tissue cytokines (72-95% less) than wild-type mice and showed less dendritic cell activation. IL-37 interacted intracellularly with Smad3 and IL-37-expressing cells and transgenic mice showed less cytokine suppression when endogenous Smad3 was depleted. IL-37 thus emerges as a natural suppressor of innate inflammatory and immune responses.

Metabolic changes during exclusive enteral nutrition in pediatric Crohn's disease patients.

BACKGROUND AND AIMS: Exclusive enteral nutrition is recommended as a first-line treatment in active pediatric Crohn's Disease, but its mechanism of action is still not clear. We aimed to assess alterations in the metabolic profile of newly diagnosed pediatric Crohn's Disease patients before and during exclusive enteral nutrition therapy. METHODS: Plasma samples from 14 pediatric Crohn's Disease patients before and after 3-4 weeks on exclusive enteral nutrition were analyzed using mass spectrometry. T-test, fold change and orthogonal partial least squares discriminant analysis were used for mining significant features. Correlation analysis was performed between the annotated features and the weighted pediatric Crohn's disease activity index using Pearson r distance. RESULTS: Among the 13 compounds which decreased during exclusive enteral nutrition, most are related to diet, while one is a bacterial metabolite, Bacteriohopane-32,33,34,35-tetrol. The phosphatidic acid metabolite PA(15:1/18:0) was significantly reduced and correlated with the weighted pediatric Crohn's disease activity index. Lipids increased during exclusive enteral nutrition therapy included phosphatidylethanolamines; PE(24:1/24:1), PE(17:2/20:2) and one lactosylceramide; LacCer(d18:1/14:0). CONCLUSION: Food additives and other phytochemicals were the major metabolites, which decreased following the exclusion of a regular diet during exclusive enteral nutrition. An alteration in bacterial biomarkers may reflect changes in intestinal microbiota composition and metabolism. Thus, metabolomics provides an opportunity to characterize the molecular mechanisms of dietary factors triggering Crohn's Disease activity, and the mechanisms of action of exclusive enteral nutrition, thereby providing the basis for the development and evaluation of improved intervention strategies for prevention and treatment.

SARS-CoV2 mRNA Vaccine-Specific B-, T- and Humoral Responses in Adolescents After Kidney Transplantation.

Protection of adult kidney transplant recipients against SARS-CoV2 was shown to be strongly impaired owing to low reactogenicity of available vaccines. So far, data on vaccination outcomes in adolescents are scarce due to later vaccination approval for this age group. We therefore comprehensively analyzed vaccination-specific humoral-, T- and B-cell responses in kidney transplanted adolescents aged 12-18 years in comparison to healthy controls 6 weeks after standard two-dose BNT162b2 ("Comirnaty"; Pfizer/BioNTech) vaccination. Importantly, 90% (18/20) of transplanted adolescents showed IgG seroconversion with 75% (15/20) developing neutralizing titers. Still, both features were significantly diminished in magnitude compared to controls. Correspondingly, spike-specific B cells were quantitatively reduced and enriched for non-isotype-class-switched IgD+27+ memory cells in patients. Whereas spike specific CD4+ T cell frequencies were similar in both groups, cytokine production and memory differentiation were significantly impaired in transplant recipients. Although our data identify limitations in all arms of vaccine-specific immunity, the majority of our adolescent patients showed robust humoral responses despite antimetabolite-based treatment being associated with poor vaccination outcomes in adults.

Expression of IL-37 Correlates With Immune Cell Infiltrate and Fibrosis in Pediatric Autoimmune Liver Diseases.

OBJECTIVES: The activation of innate immune mechanisms is key for chronic liver injury. Interleukin-37 (IL-37) is a profound inhibitor of innate and adaptive immune responses, and its overexpression protects mice from liver inflammation and fibrosis. Here, we characterize the hepatic inflammatory infiltrate and expression of IL-37 in children with autoimmune liver diseases. METHODS: We compared the inflammatory microenvironment of the liver in a retrospective cohort of children with primary sclerosing cholangitis (PSC), autoimmune sclerosing cholangitis (ASC) and autoimmune hepatitis (AIH) by immunohistochemistry. The expression of IL-37 was quantified in liver parenchyma and portal tracts. Double immunofluorescence was used for detection of IL-37 in specific cell types and colocalization with Smad3. RESULTS: AIH is characterized by a dense lymphoplasmacytic infiltrate whereas ASC shows high numbers of granulocytes in portal tracts. IL-37 expression correlates positively with liver inflammation and fibrosis, the number of infiltrating immune cells and serum markers for hepatic inflammation. IL-37 is mainly expressed in hepatocytes, cholangiocytes and infiltrating immune cells. Double staining revealed IL-37 positivity in T helper and regulatory T cells (Treg), Kupffer (KC) and hepatic stellate cells (HSC). IL-37 colocalizes with intranuclear pSmad3L in areas of liver inflammation. CONCLUSIONS: Pediatric ASC separates from PSC and AIH by a granulocyte-rich portal infiltrate. Upregulation of IL-37 with liver injury, the expression in Treg as well as KC and HSC and the colocalization of IL-37 with pSmad3L in cholangiocytes and hepatocytes suggest a modulating role to limit hepatic inflammation and fibrosis in pediatric autoimmune liver diseases.

Role for nuclear interleukin-37 in the suppression of innate immunity.

The IL-1 family member IL-37 broadly suppresses innate inflammation and acquired immunity. Similar to IL-1α and IL-33, IL-37 is a dual-function cytokine in that IL-37 translocates to the nucleus but also transmits a signal via surface membrane receptors. The role of nuclear IL-37 remains unknown on the ability of this cytokine to inhibit innate inflammation. Here, we compared suppression of innate inflammation in transgenic mice expressing native human IL-37 (IL-37Tg) with those of transgenic mice carrying the mutation of aspartic acid (D) to alanine (A) at amino acid 20 (IL-37D20ATg). The mutation D20A prevents cleavage of caspase-1, a step required for IL-37 nuclear translocation. In vitro, peritoneal macrophages from IL-37Tg mice reduced LPS-induced IL-1ß, IL-6, TNFα and IFNγ by 40-50% whereas in macrophages from IL-37D20ATg mice this suppression was not observed, consistent with loss of nuclear function. Compared with macrophages from IL-37Tg mice, significantly less or no suppression of LPS-induced MAP kinase and NFκB activation was also observed in macrophages from IL-37D20ATg mice. In vivo, levels of IL-1ß, IL-6, and TNFα in the lungs and liver were markedly reduced during endotoxemia in IL-37Tg mice but not observed in IL-37D20ATg mice. However, suppression of innate inflammation remains intact in the IL-37D20A mice once the cytokine is released from the cell and binds to its receptor. These studies reveal a nuclear function for suppression of innate inflammation and are consistent with the dual function of IL-37 and a role for caspase-1 in limiting inflammation.

Alterations of Central Liver Metabolism of Pediatric Patients with Non-Alcoholic Fatty Liver Disease.

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in children and is associated with overweight and insulin resistance (IR). Almost nothing is known about in vivo alterations of liver metabolism in NAFLD, especially in the early stages of non-alcoholic steatohepatitis (NASH). Here, we used a complex mathematical model of liver metabolism to quantify the central hepatic metabolic functions of 71 children with biopsy-proven NAFLD. For each patient, a personalized model variant was generated based on enzyme abundances determined by mass spectroscopy. Our analysis revealed statistically significant alterations in the hepatic carbohydrate, lipid, and ammonia metabolism, which increased with the degree of obesity and severity of NAFLD. Histologic features of NASH and IR displayed opposing associations with changes in carbohydrate and lipid metabolism but synergistically decreased urea synthesis in favor of the increased release of glutamine, a driver of liver fibrosis. Taken together, our study reveals already significant alterations in the NASH liver of pediatric patients, which, however, are differently modulated by the simultaneous presence of IR.

Outcome after pediatric liver transplantation for staged abdominal wall closure with use of biological mesh-Study with long-term follow-up.

Abdominal wall closure after pediatric liver transplantation (pLT) in infants may be hampered by graft-to-recipient size discrepancy. Herein, we describe the use of a porcine dermal collagen acellular graft (PDCG) as a biological mesh (BM) for abdominal wall closure in pLT recipients. Patients <2 years of age, who underwent pLT from 2011 to 2014, were analyzed, divided into definite abdominal wall closure with and without implantation of a BM. Primary end-point was the occurrence of postoperative abdominal wall infection. Secondary end-points included 1- and 5-year patient and graft survival and the development of abdominal wall hernia. In five out of 21 pLT recipients (23.8%), direct abdominal wall closure was achieved, whereas 16 recipients (76.2%) received a BM. BM removal was necessary in one patient (6.3%) due to abdominal wall infection, whereas no abdominal wall infection occurred in the no-BM group. No significant differences between the two groups were observed for 1- and 5-year patient and graft survival. Two late abdominal wall hernias were observed in the BM group vs none in the no-BM group. Definite abdominal wall closure with a BM after pLT is feasible and safe when direct closure cannot be achieved with comparable postoperative patient and graft survival rates.

Stiripentol fails to lower plasma oxalate in a dialysis-dependent PH1 patient.

BACKGROUND: Primary hyperoxaluria type 1 (PH1) is a multisystemic metabolic disorder caused by an excessive production of oxalate by the liver. The majority of patients presenting in early infancy have end-stage renal disease (ESRD). While awaiting the results of sRNAi trials, the current standard treatment is combined liver-kidney transplantation. Recently, Stiripentol has been reported as a promising drug in the treatment of primary hyperoxaluria by reducing urinary oxalate (UOx). Stiripentol is an anti-convulsive drug used in the treatment of children suffering from Dravet syndrome. It causes blockage of the last step in oxalate production by inhibition of hepatic lactate dehydrogenase 5 (LDH5). CASE: We administered Stiripentol as compassionate use in an anuric infant with dialysis-dependent PH1 over a period of 4 months. Although achieving plasma concentrations of Stiripentol that were recently reported to lower UOx excretion, we did not observe significant reduction to plasma oxalate concentrations (POx). CONCLUSION: We conclude that Stiripentol may not be useful to reduce POx in PH patients with advanced chronic kidney disease (CKD), but larger studies are needed to confirm this finding.

Single-Pass Albumin Dialysis in the Treatment of Children with Liver Failure.

BACKGROUND AND AIMS: Acute and acute on chronic liver failure are life-threatening conditions, and bridging to transplantation is complicated by a paucity of suitable organs for children. While different modalities of extracorporeal liver support exist, their use in children is complicated by a large extracorporeal volume, and data on their use in children is limited. The aim of this analysis was to investigate the efficacy and safety of single-pass albumin dialysis (SPAD) in children with liver failure. METHODS: Retrospective medical chart review of pediatric patients with liver failure treated with SPAD. The decrease in hepatic encephalopathy (HE) and the serum levels of bilirubin and ammonia were measured to determine efficacy. Adverse events were documented to assess safety. RESULTS: Nineteen pediatric patients with a median age of 25.5 months and a median body weight of 11.9 kg were treated with SPAD between January 2011 and March 2018. Total bilirubin (p < 0.001) and ammonia (p = 0.02) significantly decreased after treatment with SPAD. As clinical outcome parameter, HE significantly improved (p = 0.001). Twelve patients were bridged successfully to liver transplantation. In all patients, 71 SPAD sessions were run. Clotting in the dialysis circuit was observed in 49% of all sessions. Heparin and citrate were used for anticoagulation and were significantly superior to dialysis without any anticoagulation (p= 0.03). Transfusion of packed blood cells (57%) and catecholamine therapy (49%) were frequently necessary. CONCLUSIONS: Treatment with SPAD was effective in detoxification, as measured by significant improvement of HE and clearance from surrogate laboratory parameters.

Genetic determinants of steatosis and fibrosis progression in paediatric non-alcoholic fatty liver disease.

BACKGROUND AND AIMS: Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in children and adolescents today. In comparison with adult disease, paediatric NAFLD may show a periportal localization, which is associated with advanced fibrosis. This study aimed to assess the role of genetic risk variants for histological disease pattern and severity in childhood NAFLD. METHODS: We studied 14 single nucleotide polymorphisms (SNP) in a cohort of 70 adolescents with biopsy-proven NAFLD. Genotype was compared to an adult control cohort (n = 200) and analysed in relation to histological disease severity and liver tissue proteomics. RESULTS: Three of the 14 SNPs were significantly associated with paediatric NAFLD after FDR adjustment, rs738409 (PNPLA3, P = 2.80 × 10-06 ), rs1044498 (ENPP1, P = 0.0091) and rs780094 (GCKR, P = 0.0281). The severity of steatosis was critically associated with rs738409 (OR=3.25; 95% CI: 1.72-6.52, FDR-adjusted P = 0.0070). The strongest variants associated with severity of fibrosis were rs1260326, rs780094 (both GCKR) and rs659366 (UCP2). PNPLA3 was associated with a portal pattern of steatosis, inflammation and fibrosis. Proteome profiling revealed decreasing levels of GCKR protein with increasing carriage of the rs1260326/rs780094 minor alleles and downregulation of the retinol pathway in rs738409 G/G carriers. Computational metabolic modelling highlighted functional relevance of PNPLA3, GCKR and UCP2 for NAFLD development. CONCLUSIONS: This study provides evidence for the role of PNPLA3 as a determinant of portal NAFLD localization and severity of portal fibrosis in children and adolescents, the risk variant being associated with an impaired hepatic retinol metabolism.

Caplacizumab for relapsing thrombotic thrombocytopenic purpura.

BACKGROUND: Thrombotic thrombocytopenic purpura (TTP) is an ultra-rare disorder in childhood and belongs to the microangiopathic hemolytic anemias (MAHA) and the thrombotic microangiopathies (TMA). In the acquired form, autoantibodies against ADAMTS13 inhibit cleaving of von Willebrand factor (vWF) multimers, thereby promoting their interaction with thrombocytes, causing TMA and MAHA. A recently introduced nanobody, caplacizumab, inhibits the binding of platelets to vWF. CASE-DIAGNOSIS/TREATMENT: During a first episode, a 10-year-old girl was admitted for TTP. Plasma exchange (PE) and immunosuppressive therapy with corticosteroids and mycophenolate mofetil were initiated. The course was complicated by catheter-associated septicemia and a very slow hematological and clinical recovery. Platelet count became normal at day 40 after admission and treatment initiation. Three years later, the child presented again with TTP. During this second episode, caplacizumab was introduced together with PE and immunosuppressive therapy within 4 days after admission. With this regimen, platelet count normalized within 3 days of treatment, and PE treatment could be stopped after a total of 14 days. The child could be discharged and caplacizumab was continued on an outpatient basis until day 30 after initiation. Adverse events during the use of caplacizumab were not encountered. CONCLUSIONS: Caplacizumab treatment was safe and effective in a child with relapsing, autoantibody-mediated TTP. With respect to this potentially life-threatening condition, the add-on use of caplacizumab represents a novel option to reduce morbidity and mortality and improve quality of life in children and adolescents with TTP.

Beneficial effects of IL-37 after spinal cord injury in mice.

IL-37, a member of the IL-1 family, broadly reduces innate inflammation as well as acquired immunity. Whether the antiinflammatory properties of IL-37 extend to the central nervous system remains unknown, however. In the present study, we subjected mice transgenic for human IL-37 (hIL-37tg) and wild-type (WT) mice to spinal cord contusion injury and then treated them with recombinant human IL-37 (rIL-37). In the hIL-37tg mice, the expression of IL-37 was barely detectable in the uninjured cords, but was strongly induced at 24 h and 72 h after the spinal cord injury (SCI). Compared with WT mice, hIL-37tg mice exhibited increased myelin and neuronal sparing and protection against locomotor deficits, including 2.5-fold greater speed in a forced treadmill challenge. Reduced levels of cytokines (e.g., an 80% reduction in IL-6) were observed in the injured cords of hIL-37tg mice, along with lower numbers of blood-borne neutrophils, macrophages, and activated microglia. We treated WT mice with a single intraspinal injection of either full-length or processed rIL-37 after the injury and found that the IL-37-treated mice had significantly enhanced locomotor skills in an open field using the Basso Mouse Scale, as well as supported faster speed on a mechanical treadmill. Treatment with both forms of rIL-37 led to similar beneficial effects on locomotor recovery after SCI. This study presents novel data indicating that IL-37 suppresses inflammation in a clinically relevant model of SCI, and suggests that rIL-37 may have therapeutic potential for the treatment of acute SCI.

Ethanol-mediated suppression of IL-37 licenses alcoholic liver disease.

BACKGROUND & AIMS: Chronic alcohol consumption and alcoholic liver disease (ALD) afflicts individuals with substantial morbidity and mortality with limited treatment options available. Hepatic inflammation, triggered by activated Kupffer cells, is a driving force in alcoholic liver disease. Interleukin 37 (IL-37) exerts anti-inflammatory effects in hepatic diseases, however, the impact of Interleukin 37 on alcoholic liver disease is unknown. In this study, we addressed the role of Interleukin 37 in alcoholic liver disease. METHODS: We utilized Interleukin 37 expressing transgenic mice and human recombinant Interleukin 37 in models of alcoholic liver disease. Interleukin 37 expression was measured in liver samples of 20 alcoholic steatohepatitis and 36 non-alcoholic fatty liver disease patients. RESULTS: Interleukin 37 transgenic mice are not protected against hepatic injury and inflammation in alcoholic liver disease. Ethanol suppressed Interleukin 37 expression in transgenic mice. Alcoholic steatohepatitis (ASH) patients similarly exhibited reduced Interleukin 37 expression when compared to non-alcoholic fatty liver disease (NAFLD) patients. Human recombinant Interleukin 37 ameliorated hepatic inflammation in a binge drinking model of alcoholic liver disease. CONCLUSION: We provide evidence for an exogenous noxae that suppresses Interleukin 37 expression which limits its anti-inflammatory effects in alcoholic liver disease.

Hyperadiponectinemia During Infliximab Induction Therapy in Pediatric Crohn Disease.

OBJECTIVES: The inflammatory process in Crohn disease (CD) involves the visceral fat, characterized by adipocyte hyperplasia and altered adipose tissue and serum concentrations of tumor necrosis factor (TNF), leptin, adiponectin and resistin. We investigated the effect of anti-TNF therapy with infliximab (IFX) on serum adipokine levels in pediatric CD. METHODS: Serum concentrations of resistin (ng/mL), leptin (ng/mL), and total adiponectin (µg/mL) were assessed by enzyme-linked immunosorbent assays (ELISA) in 18 pediatric CD patients (mean age 15.0 ±â€Š1.5 years) before first, second, and fourth IFX infusion (weeks 0, 2, and 14) and compared with baseline values from sex- and BMI-matched healthy controls (HC, mean age 13.4 ±â€Š1.6 years). RESULTS: At baseline, CD patients (mean age 15.0 ±â€Š1.5 years, 10 of 18 boys) compared with HC (13.4 ±â€Š1.6 years, 7 of 15 boys) had higher resistin levels (median 14.7 ng/mL, range 5.1-50.5 vs 7.3 ng/mL, 0.5-14.5); P = 0.0002). At weeks 2 and 14, resistin decreased to 6.9 ng/mL (2.9-16.8) (P < 0.0001) and 9.2 ng/mL (4.1-20.6; P = 0.0011), respectively. Leptin and adiponectin were comparable between patients and HC at baseline. Leptin increased in girls from 9.5 ng/mL (4.0-30.1) to 16.0 ng/mL (7.9-35.2; P = 0.0156) and 17.2 ng/mL (10.8- 26.8; P = 0.1953) at weeks 0, 2, and 14 respectively; with a trend in boys from 2 (0.6-12.9) to 2.8 (1.7-8.6; P = 0.0840) and 3.3 (1.3-4.6; P = 0.1309). Adiponectin peaked initially from 7.8 µg/mL (4.6-11.9) at week 0 to 9.2 µg/mL (4.1-20.7; P = 0.0005) at week 2 and thereafter fell to 6.5 µg/mL (3.0-12.7; P = 0.0182) at week 14. CONCLUSIONS: TNF blockade is associated with changes in circulating adipokines. The marked early increase of the potent anti-inflammatory adiponectin may contribute to the rapid response to IFX in CD.