Type I interferon restricts type 2 immunopathology through the regulation of group 2 innate lymphoid cells.

Viral respiratory tract infections are the main causative agents of the onset of infection-induced asthma and asthma exacerbations that remain mechanistically unexplained. Here we found that deficiency in signaling via type I interferon receptor led to deregulated activation of group 2 innate lymphoid cells (ILC2 cells) and infection-associated type 2 immunopathology. Type I interferons directly and negatively regulated mouse and human ILC2 cells in a manner dependent on the transcriptional activator ISGF3 that led to altered cytokine production, cell proliferation and increased cell death. In addition, interferon-γ (IFN-γ) and interleukin 27 (IL-27) altered ILC2 function dependent on the transcription factor STAT1. These results demonstrate that type I and type II interferons, together with IL-27, regulate ILC2 cells to restrict type 2 immunopathology.

Natural history of post-operative non-functioning pituitary adenomas - a single centre cohort analysis.

PURPOSE: To study behaviour of endonasally operated non-functioning pituitary adenomas (NFPA) and propose a cost-effective stratified follow-up regimen. METHODS: A single centre retrospective cohort analysis from June 2009 till December 2019. All endonasally operated pituitary adenomas were identified with sub-analysis of the NFPA's. Patients of all age groups with radiological follow-up more than 30 months were included. Patients with any kind of cranial intervention performed < within 30 months of surgery were excluded. The post-operative MRI for this cohort was evaluated until either any intervention was performed or until the last follow-up. The maximal tumour diameter in any plane (mm) was measured from the MRI scans. The annual growth rate and the statistical relationship between age, sex, IHC, Ki-67, resection %, residual tumour was calculated. RESULTS: Out of 610 pituitary adenomas identified in the dataset, 116 patients met the inclusion criteria. Follow-up period ranged from 30 to 142 months (mean 78.5 months). A strong relationship existed between predicting tumour progression with first post-operative residue size (p = .001). A statistically significant relationship was found to be present between tumour growth and a residue of less than 10 mm diameter and 11-20 mm in diameter (Log rank p value .0216). On average, each patient with a residue < 5mm had MRI scans costing 976 £. CONCLUSION: Based on statistical analysis and internal validation of the growth rate of the residue, we have proposed MRI follow-up scans. These recommendations have the potential to save more than 300 £per patient towards MRI costs and can lay down a marker for defining time interval of serial scans for post-operative NFPA's.

Surrogate Humane Endpoints in Small Animal Models of Acute Lung Injury: A Modified Delphi Consensus Study of Researchers and Laboratory Animal Veterinarians.

OBJECTIVES: In many jurisdictions, ethical concerns require surrogate humane endpoints to replace death in small animal models of acute lung injury. Heterogenous selection and reporting of surrogate endpoints render interpretation and generalizability of findings between studies difficult. We aimed to establish expert-guided consensus among preclinical scientists and laboratory animal veterinarians on selection and reporting of surrogate endpoints, monitoring of these models, and the use of analgesia. DESIGN: A three-round consensus process, using modified Delphi methodology, with researchers who use small animal models of acute lung injury and laboratory animal veterinarians who provide care for these animals. Statements on the selection and reporting of surrogate endpoints, monitoring, and analgesia were generated through a systematic search of MEDLINE and Embase. Participants were asked to suggest any additional potential statements for evaluation. SETTING: A web-based survey of participants representing the two stakeholder groups (researchers, laboratory animal veterinarians). Statements were rated on level of evidence and strength of support by participants. A final face-to-face meeting was then held to discuss results. SUBJECTS: None. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Forty-two statements were evaluated, and 29 were rated as important, with varying strength of evidence. The majority of evidence was based on rodent models of acute lung injury. Endpoints with strong support and evidence included temperature changes and body weight loss. Behavioral signs and respiratory distress also received support but were associated with lower levels of evidence. Participants strongly agreed that analgesia affects outcomes in these models and that none may be necessary following nonsurgical induction of acute lung injury. Finally, participants strongly supported transparent reporting of surrogate endpoints. A prototype composite score was also developed based on participant feedback. CONCLUSIONS: We provide a preliminary framework that researchers and animal welfare committees may adapt for their needs. We have identified knowledge gaps that future research should address.

Rel-Dependent Immune and Central Nervous System Mechanisms Control Viral Replication and Inflammation during Mouse Herpes Simplex Encephalitis.

Herpes simplex encephalitis (HSE), caused by HSV type 1 (HSV-1) infection, is an acute neuroinflammatory condition of the CNS and remains the most common type of sporadic viral encephalitis worldwide. Studies in humans have shown that susceptibility to HSE depends in part on the genetic make-up of the host, with deleterious mutations in the TLR3/type I IFN axis underlying some cases of childhood HSE. Using an in vivo chemical mutagenesis screen for HSV-1 susceptibility in mice, we identified a susceptible pedigree carrying a causal truncating mutation in the Rel gene (RelC307X ), encoding for the NF-κB transcription factor subunit c-Rel. Like Myd88-/- and Irf3-/- mice, RelC307X mice were susceptible to intranasal HSV-1 infection. Reciprocal bone marrow transfers into lethally irradiated hosts suggested that defects in both hematopoietic and CNS-resident cellular compartments contributed together to HSE susceptibility in RelC307X mice. Although the RelC307X mutation maintained cell-intrinsic antiviral control, it drove increased apoptotic cell death in infected fibroblasts. Moreover, reduced numbers of CD4+CD25+Foxp3+ T regulatory cells, and dysregulated NK cell and CD4+ effector T cell responses in infected RelC307X animals, indicated that protective immunity was also compromised in these mice. In the CNS, moribund RelC307X mice failed to control HSV-1 viral replication in the brainstem and cerebellum, triggering cell death and elevated expression of Ccl2, Il6, and Mmp8 characteristic of HSE neuroinflammation and pathology. In summary, our work implicates c-Rel in both CNS-resident cell survival and lymphocyte responses to HSV-1 infection and as a novel cause of HSE disease susceptibility in mice.

Giant extradural spinal schwannoma in a non-neurofibromatosis child-case report and review of literature.

Spinal schwannoma is a rare occurrence in non-neurofibromatosis (NF) pediatric patients, especially in the extradural space extending beyond two vertebral levels. Within this age group, the common extradural tumors are either soft tissue sarcomas or metastasis, often with vertebral bony involvement. Spinal schwannomas are usually benign, slowly progressive, well-defined, intradural extramedullary lesion showing homogenous contrast enhancement on imaging. Though its clinical presentation may be with marked neurological involvement, timely surgical excision usually leads to a quick recovery of the deficits in the young age.This case report describes a giant, spinal, benign schwannoma in a 6-year-old boy which was extradural in location. The lesion was resected completely, and since then, he has been asymptomatic, tumor-free for over 3 years.

Endonasal endoscopic skullbase surgery in children.

OBJECTIVE: The role of endonasal endoscopic approach for pathologies in the paediatric population is evolving and has still not been accepted as standard of care in neurosurgery. It represents a challenge in terms of narrow access, instrument manipulation and adequate reconstruction of defects. We have described our experience in 49 cases from a single neurosurgical unit in paediatric skull base surgeries through this approach over the last 12 years. MATERIAL AND METHODS: A case series of 59 paediatric skull base surgeries in 49 children through endoscopic endonasal route over the last 12 years is presented. The age ranges from 4 months to 18 years. Out of 49 cases, 22 cases were of craniopharyngiomas, 8 cases of pituitary adenomas, 5 cases with CSF rhinorrhea, 5 cases with meningoencephalocele, 3 cases of Rathke's cleft cysts, 2 cases of odontoidectomy and 4 miscellaneous cases viz. mucocele, hypothalamic glioma, esthesioneuroblastoma and epidermoid. CSF leaks were repaired with free graft in the initial years and by vascularized flap more recently. RESULTS: The goal of surgery was achieved in all but two cases in whom the tumour excision was unsatisfactory due to failure of the cyst wall to collapse after decompression. Extent of tumour excision was not compromised by the choice of this approach. Revision surgery for CSF leak was required in three patients. Local vascularized nasoseptal flap has been possible even in very young patients and has now become the standard for reconstruction. CONCLUSION: In spite of the challenges posed by small nostrils and ill-developed sinuses in the paediatric age group, surgery from endoscopic endonasal corridor is possible to be carried out successfully in selected cases.

Tumour-induced Osteomalacia Secondary to Intracranial Tumours - Report of 2 Cases.

Tumor induced osteomalacia (TIO) is a paraneoplastic syndrome which is mostly caused by a phosphaturic mesenchymal tumour mixed connective tissue variant (PMTMCT). These tumours do not have any specific site predilection but their presence in cranial compartment is very rare. Two cases of TIO secondary to phosphaturic mesenchymal tumour at the skull base are described ahead, one of which was in the posterior fossa and the other in middle cranial fossa. Early diagnosis and complete excision of PMT is essential in preventing morbidity secondary to osteomalacia. This case report stands distinct in highlighting a rare site of a phosphaturic mesenchymal tumour and the need to keep a high index of suspicion in cases of TIO especially wherein localization of the tumour is unsuccessful.

Regulation of ULK1 Expression and Autophagy by STAT1.

Autophagy involves the lysosomal degradation of cytoplasmic contents for regeneration of anabolic substrates during nutritional or inflammatory stress. Its initiation occurs rapidly after inactivation of the protein kinase mammalian target of rapamycin (mTOR) (or mechanistic target of rapamycin), leading to dephosphorylation of Unc-51-like kinase 1 (ULK1) and autophagosome formation. Recent studies indicate that mTOR can, in parallel, regulate the activity of stress transcription factors, including signal transducer and activator of transcription-1 (STAT1). The current study addresses the role of STAT1 as a transcriptional suppressor of autophagy genes and autophagic activity. We show that STAT1-deficient human fibrosarcoma cells exhibited enhanced autophagic flux as well as its induction by pharmacological inhibition of mTOR. Consistent with enhanced autophagy initiation, ULK1 mRNA and protein levels were increased in STAT1-deficient cells. By chromatin immunoprecipitation, STAT1 bound a putative regulatory sequence in the ULK1 5'-flanking region, the mutation of which increased ULK1 promoter activity, and rendered it unresponsive to mTOR inhibition. Consistent with an anti-apoptotic effect of autophagy, rapamycin-induced apoptosis and cytotoxicity were blocked in STAT1-deficient cells but restored in cells simultaneously exposed to the autophagy inhibitor ammonium chloride. In vivo, skeletal muscle ULK1 mRNA and protein levels as well as autophagic flux were significantly enhanced in STAT1-deficient mice. These results demonstrate a novel mechanism by which STAT1 negatively regulates ULK1 expression and autophagy.

Frequent and differential mutations of the CYLD gene in basal cell salivary neoplasms: linkage to tumor development and progression.

Basal cell salivary neoplasms display similar cyto-morphologic features and are classified into adenoma and adenocarcinoma based on the presence or absence of tumor invasion at diagnosis. These neoplasms also share considerable phenotypic resemblance and co-exist with certain dermal adnexal tumors harboring the CYLD gene mutations inferring common genetic association. We sequenced the CYLD gene in both basal cell adenomas and adenocarcinomas and correlated the findings with CYLD, NF-κB, and ß-catenin expression levels and clinicopathologic factors. Twenty mutations were identified and comprised of 3 synonymous and 17 non-synonymous (missense) types involving the coding exons of the CYLD gene. Mutations in exons 9-11 were identified in both adenomas and adenocarcinomas, while mutations in exons 12-20, encoding the USP domain, were exclusively found in carcinomas. Although no significant correlation between CYLD mutations and expression levels of CYLD, NF-κB, and ß-catenin or clinicopathologic parameters was found, basal cell adenocarcinomas with multiple mutations showed reduction in CYLD protein expression and pursued aggressive clinical behavior. Our study revealed high incidence and sequential CYLD mutations in both basal cell adenoma and adenocarcinoma supporting a single neoplastic continuum for their evolution and provides evidence for potential diagnostic and therapeutic utility.

The TLR4-TRIF pathway can protect against the development of experimental allergic asthma.

The Toll-like receptor (TLR) adaptor proteins myeloid differentiating factor 88 (MyD88) and Toll, interleukin-1 receptor and resistance protein (TIR) domain-containing adaptor inducing interferon-ß (TRIF) comprise the two principal limbs of the TLR signalling network. We studied the role of these adaptors in the TLR4-dependent inhibition of allergic airway disease and induction of CD4+ ICOS+ T cells by nasal application of Protollin™, a mucosal adjuvant composed of TLR2 and TLR4 agonists. Wild-type (WT), Trif-/- or Myd88-/- mice were sensitized to birch pollen extract (BPEx), then received intranasal Protollin followed by consecutive BPEx challenges. Protollin's protection against allergic airway disease was TRIF-dependent and MyD88-independent. TRIF deficiency diminished the CD4+ ICOS+ T-cell subsets in the lymph nodes draining the nasal mucosa, as well as their recruitment to the lungs. Overall, TRIF deficiency reduced the proportion of cervical lymph node and lung CD4+ ICOS+ Foxp3- cells, in particular. Adoptive transfer of cervical lymph node cells supported a role for Protollin-induced CD4+ ICOS+ cells in the TRIF-dependent inhibition of airway hyper-responsiveness. Hence, our data demonstrate that stimulation of the TLR4-TRIF pathway can protect against the development of allergic airway disease and that a TRIF-dependent adjuvant effect on CD4+ ICOS+ T-cell responses may be a contributing mechanism.

Gram-positive pneumonia augments non-small cell lung cancer metastasis via host toll-like receptor 2 activation.

Surgical resection of early stage nonsmall cell lung cancer (NSCLC) is necessary for cure. However, rates of postoperative bacterial pneumonias remain high and may confer an increased risk for metastasis. Toll-like receptors (TLRs) mediate the inflammatory cascade by recognizing microbial products at the surface of numerous cell types in the lung; however, little is known about how host TLRs influence NSCLC metastasis. TLR2 recognizes gram-positive bacterial cell wall components activating innate immunity. We demonstrate that lower respiratory tract infection with Streptococcus pneumonia augments the formation of murine H59 NSCLC liver metastases in C57BL/6 mice through host TLR2 activation. Infected mice demonstrate increased H59 and human A549 NSCLC adhesion to hepatic sinusoids in vivo compared with noninfected controls, a response that is significantly diminished in TLR2 knock-out mice. Intra-tracheal injection of purified TLR2 ligand lipoteichoic acid into mice similarly augments in vivo adhesion of H59 cells to hepatic sinusoids. Additionally, H59 and A549 NSCLC cells incubated with bronchoepithelial conditioned media show increased cell adhesion to extracellular matrix components in vitro and hepatic sinusoids in vivo in a manner that is dependent on bronchoepithelial TLR2 activation and interleukin-6 secretion. TLR2 is therefore a potential therapeutic target for gram-positive pneumonia-driven NSCLC metastasis.

Divergent impact of Toll-like receptor 2 deficiency on repair mechanisms in healthy muscle versus Duchenne muscular dystrophy.

Injury to skeletal muscle, whether acute or chronic, triggers macrophage-mediated innate immunity in a manner which can be either beneficial or harmful for subsequent repair. Endogenous ligands for Toll-like receptor 2 (TLR2) are released by damaged tissues and might play an important role in activating the innate immune system following muscle injury. To test this hypothesis, we compared macrophage behaviour and muscle repair mechanisms in mice lacking TLR2 under conditions of either acute (cardiotoxin-induced) or chronic (mdx mouse genetic model of Duchenne muscular dystrophy; DMD) muscle damage. In previously healthy muscle subjected to acute damage, TLR2 deficiency reduced macrophage numbers in the muscle post-injury but did not alter the expression pattern of the prototypical macrophage polarization markers iNOS and CD206. In addition, there was abnormal persistence of necrotic fibres and impaired regeneration in TLR2-/- muscles after acute injury. In contrast, TLR2 ablation in chronically diseased muscles of mdx mice not only resulted in significantly reduced macrophage numbers but additionally modified their phenotype by shifting from inflammatory (iNOS(pos) CD206(neg) ) to more anti-inflammatory (iNOS(neg) CD206(pos) ) characteristics. This decrease in macrophage-mediated inflammation was associated with ameliorated muscle histopathology and improved force-generating capacity of the dystrophic muscle. Our results suggest that the role of TLR2 in macrophage function and skeletal muscle repair depends greatly upon the muscle injury context, and raise the possibility that inhibition of TLR2 could serve as a useful therapeutic measure in DMD.

Primary intraventricular meningiomas in children-experience of two cases with review of literature.

Meningiomas are rare in the pediatric age group, more so in the intraventricular location. They arise in the lateral ventricles from the arachnoid cells contained within the choroid plexus, in the third ventricle from the velum interpositum and in the fourth ventricle from the choroids. These tumors are usually large and have an aggressive behaviour. Surgical management of intra-ventricular meningiomas is challenging because of their deep location, large size at presentation and increased vascularity. The authors report two such cases who presented with symptoms of raised intra cranial pressure and on evaluation were found to have associated hydrocephalus. Both these patients underwent surgical excision of the tumour by frontal transcortical approach and histopathology report confirmed transitional meningioma in them. Only twenty seven cases of intraventricular meningiomas in children have been reported till date. Their definitive treatment is surgery alone and total excision of the tumor is curative. Possibility of neurofibromatosis as a differential should also be considered in their management.

A comparison of quality of sleep between patients with chronic kidney disease not on hemodialysis and end-stage renal disease on hemodialysis in a developing country.

Few studies have compared quality of sleep between pre-dialysis chronic kidney disease (pre-dialysis CKD) patients and end-stage renal disease patients on dialysis (ESRD) and have found inconsistent results. Objective of this study is to compare quality of sleep between patients with pre-dialysis CKD and ESRD in a developing country. This study was conducted in an out-patient department and hemodialysis unit of a tertiary care facility. Patients included had either pre-dialysis CKD or ESRD. Assessment of quality of sleep was done using Pittsburgh sleep quality index (PSQI). A total of 152 patients were included in the study. Out of these patients, 79 (52%) had ESRD and 73 (48%) had pre-dialysis CKD. Median PSQI score was 6 (IQR 3-8.8). Poor sleep quality (PSQI ≥5) was present in 100 (65.8%) patients. Only hemoglobin (ß = -0.39, p < .01), depression (ß = 0.56, p < .01) and history of cardiovascular disease (ß = 0.22, p < .01) were associated with PSQI global score in a multiple linear regression analysis. There was no significant association between ESRD vs. pre-dialysis CKD and PSQI global scores and no significant co-relation between eGFR and global PSQI score (r = -0.34, p value .80) in pre-dialysis CKD patients. Poor sleep quality is common in patients with CKD including hemodialysis patients in a developing country, which is independent of kidney function in non-dialysis patients. There is no difference in quality of sleep between pre-dialysis CKD and ESRD patients.

Prognostic value of preoperative neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio in patients with epithelial ovarian cancer.

PURPOSE: The neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) have recently been evaluated in many cancers in prediction of survival outcomes. The purpose of this study was to investigate the impact of NLR and PLR on the prognosis of patients with epithelial ovarian cancer (EOC). MATERIALS AND METHODS: A total of 208 patients with EOC were included in the study. Hematological parameters and clinicopathological data during diagnosis were retrospectively evaluated. The cut-off values were determined by calculating receiver operating characteristic (ROC) curve analysis of the patients. RESULTS: The median over-all survival (OS) of patients with low NLR was 69 months (95% CI, 43.0-94.9) whereas high NLR was 36 months (95% CI, 29.1-42.8). The median OS with low PLR patients was 76 months (95% CI, 46.4-105.5) and high PLR was 35 months (95% CI, 28.5-41.4). In serous tumors (70.7%), the median OS with low NLR and high NLR was 54 months (95% CI, 27.9-80.0) and 34 months (95% CI, 28.2-39.7), and for the median OS with low PLR and high PLR it was 51 months (95% CI, 2 1.2-80.7) and 35 months (95% CI, 27.8-42.1), respectively. CONCLUSION: The present findings showed that the high NLR and high PLR were associated with poor prognosis and these values are significantly remarkable in EOC patients.

A comparison of anxiety and depression between pre-dialysis chronic kidney disease patients and hemodialysis patients using hospital anxiety and depression scale.

OBJECTIVE: Tocompare frequency of anxiety and depression between pre-dialysis chronic kidney disease (CKD) and hemodialysis patients (ESRD) in Pakistan. METHODS: This study was conducted in an out-patient department and hemodialysis unit of Sharif Medical City Hospital. Inclusion criteria included age above 18 years and a diagnosis of CKD including both pre-dialysis CKD and ESRD patients. Patients were screened for anxiety and depression using hospital anxiety and depression scale (HADS). RESULTS: A total of 156 patients were included in the study. Out of these patients, 81 (51.9%) had ESRD and 75 (48.1%) had pre-dialysis CKD. Mean age of all patient was 47.3±18.3 years, 96 (61.5%) were males and 60 (38.5%) were females. Median duration of renal disease was 16 months (IQR 8-36 months). Anxiety and depression were present in 111 (71.2%) and 113 (72.4%) of all patients respectively. Moderate to severe anxiety and depression were present in 54 (34.6%) and 60 (38.5%) patients respectively. In multiple logistic regression model, after adjusting for other variables, ESRD vs. pre-dialysis CKD was significantly associated with moderate to severe depression (AOR 2.26 (1.1-5.1). CONCLUSION: Both anxiety and depression are common in pre-dialysis CKD and ESRD patients. Patients with ESRD have higher frequency of depression compared to pre-dialysis CKD patients.

The Cnes2 locus on mouse chromosome 17 regulates host defense against cryptococcal infection through pleiotropic effects on host immunity.

The genetic basis of natural susceptibility to progressive Cryptococcus neoformans infection is not well understood. Using C57BL/6 and CBA/J inbred mice, we previously identified three chromosomal regions associated with C. neoformans susceptibility (Cnes1, Cnes2, and Cnes3). To validate and characterize the role of Cnes2 during the host response, we constructed a congenic strain on the C57BL/6 background (B6.CBA-Cnes2). Phenotypic analysis of B6.CBA-Cnes2 mice 35 days after C. neoformans infection showed a significant reduction of fungal burden in the lungs and spleen with higher pulmonary expression of gamma interferon (IFN-γ) and interleukin-12 (IL-12), lower expression of IL-4, IL-5, and IL-13, and an absence of airway epithelial mucus production compared to that in C57BL/6 mice. Multiparameter flow cytometry of infected lungs also showed a significantly higher number of neutrophils, exudate macrophages, CD11b(+) dendritic cells, and CD4(+) cells in B6.CBA-Cnes2 than in C57BL/6 mice. The activation state of recruited macrophages and dendritic cells was also significantly increased in B6.CBA-Cnes2 mice. Taken together, these findings demonstrate that the Cnes2 interval is a potent regulator of host defense, immune responsiveness, and differential Th1/Th2 polarization following C. neoformans infection.

Gram negative bacteria increase non-small cell lung cancer metastasis via Toll-like receptor 4 activation and mitogen-activated protein kinase phosphorylation.

Surgery is required for the curative treatment of lung cancer but is associated with high rates of postoperative pneumonias predominantly caused by gram negative bacteria. Recent evidence suggests that these severe infectious complications may decrease long term survival after hospital discharge via cancer recurrence, but the mechanism is unclear. Lung cancer cells have recently been demonstrated to express Toll-like receptors (TLR) that mediate pathogen recognition. We hypothesized that incubation of non-small cell lung cancer (NSCLC) cells with heat-inactivated Escherichia coli can augment cancer cell adhesion, migration and metastasis via TLR4 signaling. Incubation of murine and human NSCLC cells with E. coli increased in vitro cell adhesion to collagen I, collagen IV and fibronectin, and enhanced in vitro migration. Using hepatic intravital microscopy, we demonstrated that NSCLC cells have increased in vivo adhesion to hepatic sinusoids after coincubation with gram negative bacteria. These enhanced cell adhesion and migration phenotypes following incubation with E. coli were attenuated at three levels: inhibition of TLR4 (Eritoran), p38 MAPK (BIRB0796) and ERK1/2 phosphorylation (PD184352). Incubation of murine NSCLC cells in vitro with E. coli prior to intrasplenic injection significantly augmented formation of in vivo hepatic metastases 2 weeks later. This increase was abrogated by NSCLC TLR4 blockade using Eritoran. TLR4 represents a potential therapeutic target to help prevent severe postoperative infection driven cancer metastasis.

Dose-dependent effects of IL-17 on IL-13-induced airway inflammatory responses and airway hyperresponsiveness.

The Th2 cytokine IL-13 regulates several aspects of the asthmatic phenotype, including airway inflammation, airway hyperresponsiveness, and mucus production. The Th17 cytokine IL-17A is also implicated in asthma and has been shown to both positively and negatively regulate Th2-dependent responses in murine models of allergic airways disease. Our objective in this study was to better understand the role of IL-17 in airway inflammation by examining how IL-17 modifies IL-13-induced airway inflammatory responses. We treated BALB/c mice intranasally with IL-13 or IL-17 alone or in combination for 8 consecutive days, after which airway hyperresponsiveness, inflammatory cell influx into the lung, and lung chemokine/cytokine expression were assessed. As expected, IL-13 increased airway inflammation and airway hyperresponsiveness. IL-13 also increased numbers of IL-17-producing CD4(+) and γδ T cells. Treating mice with a combination of IL-13 and IL-17 reduced infiltration of IL-17(+) γδ T cells, but increased the number of infiltrating eosinophils. In contrast, coadministration of IL-13 with a higher dose of IL-17 decreased all IL-13-induced inflammatory responses, including infiltration of both IL-17(+)CD4(+) and γδ T cells. To examine the inhibitory activity of IL-17-expressing γδ T cells in this model, these cells were adoptively transferred into naive recipients. Consistent with an inhibitory role for γδ T cells, IL-13-induced infiltration of eosinophils, lymphocytes, and IL-17(+)CD4(+) T cells was diminished in recipients of the γδ T cells. Collectively, our data indicate that allergic airway inflammatory responses induced by IL-13 are modulated by both the quantity and the cellular source of IL-17.

IL-33 signaling regulates innate and adaptive immunity to Cryptococcus neoformans.

Susceptibility to progressive infection with the fungus Cryptococcus neoformans is associated with an allergic pattern of lung inflammation, yet the factors that govern this host response are not clearly understood. Using a clinically relevant mouse model of inhalational infection with virulent C. neoformans H99, we demonstrate a role for IL-33-dependent signaling in host immune defense. Infection of BALB/c mice with 10(4) CFU of C. neoformans H99 caused a time-dependent induction of IL-33 with accumulation of type 2 pulmonary innate lymphoid cells and alternatively activated macrophages in the lungs as well as Th2-polarized CD4(+) T cells in draining lymph nodes. IL-33R subunit T1/ST2-deficient (T1/ST2(-/-)) mice infected with C. neoformans H99 had improved survival with a decreased fungal burden in the lungs, spleen, and brain, compared with wild-type mice. Signaling through T1/ST2 was required for the accumulation and early production of IL-5 and IL-13 by lung type 2 pulmonary innate lymphoid cells. Further analysis of T1/ST2(-/-) mice revealed increased fungicidal exudate macrophages in the lungs and decreased C. neoformans-specific Th2 cells in the mediastinal lymph nodes. T1/ST2 deficiency also diminished goblet cell hyperplasia, mucus hypersecretion, bronchoalveolar lavage eosinophilia, alternative activation of macrophages, and serum IgE. These observations demonstrate that IL-33-dependent signaling contributes to the expansion of innate type 2 immunity and subsequent Th2-biased lung immunopathology that facilitates C. neoformans growth and dissemination.