The production, function, and clinical applications of IL-33 in type 2 inflammation-related respiratory diseases.

Epithelial-derived IL-33 (Interleukin-33), as a member of alarm signals, is a chemical substance produced under harmful stimuli that can promote innate immunity and activate adaptive immune responses. Type 2 inflammation refers to inflammation primarily mediated by Type 2 helper T cells (Th2), Type 2 innate lymphoid cells (ILC2), and related cytokines. Type 2 inflammation manifests in various forms in the lungs, with diseases such as asthma and chronic obstructive pulmonary disease chronic obstructive pulmonary disease (COPD) closely associated with Type 2 inflammation. Recent research suggests that IL-33 has a promoting effect on Type 2 inflammation in the lungs and can be regarded as an alarm signal for Type 2 inflammation. This article provides an overview of the mechanisms and related targets of IL-33 in the development of lung diseases caused by Type 2 inflammation, and summarizes the associated treatment methods. Analyzing lung diseases from a new perspective through the alarm of Type 2 inflammation helps to gain a deeper understanding of the pathogenesis of these related lung diseases. This, in turn, facilitates a better understanding of the latest treatment methods and potential therapeutic targets for diseases, with the expectation that targeting lL-33 can propose new strategies for disease prevention.

Epithelial Interleukin-1 Receptor-Like-1 Activation Is Contingent on Interleukin-33 Isoforms and Asthma-Related Receptor Variation.

INTRODUCTION: The interleukin-33/interleukin-1 receptor-like-1 (IL-33/IL1RL1) signalling pathway is implicated in asthma pathogenesis, with IL1RL1 nonsynonymous genetic polymorphisms associated with disease risk. We aimed to determine these variants' effect on IL1RL1 signalling induced by different IL33 isoforms thought to be elevated in the asthmatic airway. METHOD: In a project funded by GSK plc, which has developed an IL-33 receptor inhibitor for asthma treatment, human embryonic kidney 293 (HEK293) cells expressing secreted embryonic alkaline phosphatase (SEAP) driven by a nuclear factor kappa-beta (NF-κB) promoter, were transiently transfected with IL1RL1, containing one of four extracellular and Toll/interleukin 1 receptor (TIR) domain haplotypes. Cells were stimulated with seven different splice and proteolytic-generated IL-33 isoforms (0.001-50 ng/mL) for 24 h. Supernatant SEAP activity and interleukin-8 (IL-8) levels were determined. Primary human bronchial epithelial cells (HBECs) representing different genotype carriers were stimulated with IL-33112-270 (50 ng/mL) and induced IL-8 mRNA expression measured. RESULTS: HEK293 cells carrying both asthma extracellular and TIR domain IL1RL1 risk haplotypes presented maximal IL33-driven signalling, with minimal signalling after IL-33 activation in other protective haplotypes. All IL-33 isoforms activated IL1RL1 but with differing magnitudes. Proteolytically cleaved IL3395-270 and IL33106-270 had the greatest effect and the IL33113-270, and Exon 3,4 deletion isoform exhibited the lowest. The effect of extracellular and TIR domain genetic variants on receptor signalling was replicated in primary HBECs. Maximal IL1RL1 signalling was observed in cells carrying both extracellular and TIR signalling domain risk haplotypes. CONCLUSIONS: Overall, our study suggests asthma patients carrying the extracellular and TIR domain risk haplotype and have a lung microenvironment that promotes elevated levels of cleaved IL33, particularly where IL3395-270 and IL33106-270 may be more amenable to IL33/IL1RL1 targeting.

IL-33/ST2 enhances MMP-12 expression by macrophages to mediate inflammatory and immune response in IgG4-Related Ophthalmic Disease.

IgG4-Related Ophthalmic Disease (IgG4-ROD) is a chronic autoimmune-mediated fibrotic disease that predominantly affects the lacrimal glands, often leading to loss of function in the involved tissues or organs. Recent studies have demonstrated that MMP-12 is highly expressed in IgG4-ROD and plays a significant role in regulating immune responses. In this study, we reviewed nine patients diagnosed with IgG4-ROD based on clinical manifestations and histological analysis, and we investigated the expression of IL-33/ST2 and MMP-12 in IgG4-ROD lacrimal gland tissues using IHC. We found that IL-33 interacts with its specific receptor ST2, both of which are significantly overexpressed in IgG4-ROD tissues. Additionally, we successfully constructed a mouse model by introducing the LatY136F mutation into C57BL/6 mice to mimic IgG4-ROD lacrimal gland involvement, which helped elucidate the mechanisms involved in the induction of MMP-12. Furthermore, immunofluorescence staining confirmed that most MMP-12+ cells were derived from M2 macrophages, and an ELISA assay demonstrated that IL-33 upregulates MMP-12 in IgG4-ROD. Collectively, these data suggest that the IL-33/ST2/MMP-12 signaling pathway is activated in IgG4-ROD, with IL-33/ST2 potentially promoting M2 macrophage polarization and activation to produce MMP-12, which may serve as a novel therapeutic target for IgG4-ROD.

Bifidobacterium breve DSM 32583 and Limosilactobacillus fermentum CECT5716 postbiotics attenuate S. aureus and IL-33-induced Th2 responses.

Over the past decades, the prevalence of allergic diseases noticeably increased in industrialized countries. The Th2 immune response plays a central role in these pathologies and its modulation using pro-/postbiotics constitutes a promising approach to prevent or alleviate disease symptoms. The aim of this in vitro study, was to investigate the ability of human milk-derived Bifidobacterium breve DSM 32583 (Bb) and Limosilactobacillus fermentum CECT5716 (Lf), to modulate the Th2 induced responses. To this end, Th2 cells were generated by co-culturing of human naïve Th cells with monocyte-derived dendritic cells (moDCs) either stimulated with Staphylococcus aureus or IL-33. The immunomodulatory effects of pro-/postbiotic preparations of Bb and Lf on moDCs and Th2 cells were evaluated in terms of maturation markers expression and cytokines production. Remarkably, the tested strains induced the anti-inflammatory cytokine IL-10 in moDCs, in a strain-, dose- and viability-dependent manner with no significant upregulation of IL-12p70 nor CD83, CD86 or HLA-DR. Interestingly, Bb and Lf postbiotics were able to dampen the Th2/Th1 response induced upon S. aureus- or IL-33 stimulation. They were also able to synergistically induce IL-10 in moDCs and T cells, upon co-stimulation with LPS. Finally, we observed that live probiotics triggered a mild Th1 response that was attenuated in the presence of galacto-oligosaccharides. Altogether, Bb and Lf pro-/postbiotics exhibited remarkable immune regulatory effects on both moDCs and Th2 cells. Therefore, further in vivo studies should be considered to validate these findings and assess their ability to prevent allergy or alleviate its symptoms in affected patients.

Characterization of long-term interleukin-33 administration as an animal model of pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is characterized by the severe obstruction of the small pulmonary arteries and concomitant high pulmonary arterial pressure, resulting in progressive right ventricular failure. Previously, we demonstrated that long-term interleukin (IL)-33 administration in mice induces severe occlusive medial hypertrophy of pulmonary arteries (PA) in the lungs, which is mediated by group 2 innate lymphoid cells (ILC2s). In response to IL-33, ILC2s accumulate around the blood vessels and produce IL-5, leading to perivascular eosinophil recruitment. In this study, we characterized IL-33-induced medial hypertrophy of PA. We demonstrated that long-term IL-33 administration causes an increase in right ventricular pressure. In IL-33-deficient mice, medial hypertrophy of PA mediated by eggs of Schistosoma mansoni was attenuated, accompanied by a partial reduction in ILC2s, eosinophils, and CD4+ T cells. In addition, proteomic analysis revealed dramatic changes in the urine samples from mice treated with IL-33 or S. mansoni eggs. Resistin-like alpha (RELMα), a pulmonary hypertension-related molecule, was commonly detected in the urine in both treatments. Large amounts of RELMα were observed in the lungs of the IL-33-treated mice. These observations suggest that IL-33-induced medial hypertrophy of PA is a useful model for studying the mechanism underlying the development of PAH and finding biomarkers to indicate the onset of PAH.

Interleukin-1 family cytokines and soluble receptors in hidradenitis suppurativa.

Hidradenitis suppurativa (HS) is a chronic skin disease, characterized by clinical inflammation of the hair follicle with the recurrence of abscesses, nodules, and tunnels. Recently, several studies suggested a role of IL-1 family (IL-1F) cytokines in eliciting and sustaining the disease. The aim of this work is to perform a comprehensive analysis of IL-1F cytokines, soluble inhibitors and receptors in a cohort of HS patients not treated with biological agents. Sixteen patients affected by HS and 16 healthy controls were recruited; clinical data were collected and disease severity evaluated by means of the International HS Severity Score System (IHS4). Serum levels of IL-1F cytokines, inhibitors and receptors were measured using a Multiplex Assays. IL-18 and free IL-18 levels were significantly higher in patients vs controls. Among soluble inhibitors, IL-1Ra, IL-1R2 and ST2/IL-1R4 were significantly increased. IL-18, free IL-18 and IL-33 levels are strongly correlated with IHS4. Also the inhibitors IL-1Ra and IL-18BP show a correlation with IHS4. The data obtained in this study confirm the involvement of IL-1F cytokines in mediating the disease and determining its severity and suggest a possible role for IL-18 as novel serum biomarker of active disease.

Tissue-specific inducible IL-33 expression elicits features of eosinophilic esophagitis.

BACKGROUND: IL-33 is a type 2 inflammatory cytokine that is elevated in the esophageal epithelium of EoE subjects. We previously developed a mouse model of EoE dependent on constitutive overexpression of IL-33 from the esophageal epithelium (EoE33). OBJECTIVE: Our objective was to develop an inducible, IL-33-dependent model of EoE and examine induction of EoE-associated pathology. METHODS: We utilized a tetracycline-inducible system to express IL-33 in the esophagus by generating two transgenic mice. The first (iSophagus) expresses a reverse tetracycline transactivator (rtTA) from the esophageal epithelium. The second (TRE33) features a tetracycline-response element driving expression of IL-33. When crossed, these mice generate an inducible model of EoE (iEoE33). Mice were administered doxycycline-infused chow for up to 2 weeks. Cytokines were assessed by ELISA or bead-based multiplex. T cells were assessed by flow cytometry. Pathology was assessed by histology and immunohistochemistry for IL-33, eosinophil peroxidase, CD4, and Ki-67. iEoE33 was treated with steroids and crossed with IL-13-/- mice. For detailed Methods, please see the Methods section in this article's Online Repository at www.jacionline.org. RESULTS: Doxycycline-treated iEoE33 mice demonstrated expression of IL-33 in the esophageal epithelium, and esophageal pathology including eosinophilia, CD4+ cell infiltrate, basal zone hyperplasia, and dilated intercellular spaces. These findings became pronounced on day 7 of induction, were accompanied by weight loss and esophageal thickening, and were steroid responsive and IL-13 dependent. CONCLUSION: Inducible IL-33 expression in the esophageal epithelium elicited features pathognomonic of EoE. iEoE33 enables investigation of EoE disease mechanisms as well as initiation, progression, and resolution.

IL-33 relieves nerve injury by mediating microglial polarization in neuromyelitis optica spectrum disorders via the IL-33/ST2 pathway.

Interleukin-33 (IL-33) is a member of the interleukin-1 cytokine family. Its function in regulating microglial M1/M2 polarization in neuromyelitis optica spectrum disorder (NMOSD) is still unelucidated. To evaluate the role of IL-33 in NMOSD, we constructed NMOSD mice model by injecting purified serum IgG from AQP4-IgG seropositive NMOSD patients into experimental autoimmune encephalomyelitis (EAE) mice, and IL-33 was intraperitoneally injected into NMOSD mice 3 d before the model induction. We found that pretreatment of the NMOSD mice with IL-33 relieved brain neuron loss, and demyelination and improved the structure of axons, astrocytes, and mitochondria. In the neuronal and microglial coculture system, pretreatment with IL-33 in microglia alleviated NMOSD serum-induced inflammation and damaged morphology in cultured neurons. IL-33 transformed microglia to the M2 phenotype, and NMOSD serum promoted microglia to the M1 phenotype in cultured BV2 cells. Moreover, IL-33 influenced microglial polarity via the IL-33/ST2 pathway. IL-33 may be a novel insight useful for further developing NMOSD-targeted therapy and drug development.

IL-33/ST2 induces macrophage-dependent ROS production and TRPA1 activation that mediate pain-like responses by skin incision in mice.

Background: Insufficiently managed incisional (INC) pain severely affects patients' life quality and rehabilitation after a major operation. However, mechanisms underlying INC pain still remain poorly understood. Methods: A mouse model of INC pain was established by skin plus deep muscle incision. Biochemistry assay, in vivo reactive oxygen species (ROS) imaging, Ca2+ imaging combined with retrograde labelling, neuron tracing and nocifensive behavior test, etc. were utilized for mechanism investigation. Results: We found pro-nociceptive cytokine interleukin -33 (IL-33) ranked among top up-regulated cytokines in incised tissues of INC pain model mice. IL-33 was predominantly expressed in keratinocytes around the incisional area. Neutralization of IL-33 or its receptor suppression of tumorigenicity 2 protein (ST2) or genetic deletion of St2 gene (St2 -/-) remarkably ameliorated mechanical allodynia and improved gait impairments of model mice. IL-33 contributes to INC pain by recruiting macrophages, which subsequently release ROS in incised tissues via ST2-dependent mechanism. Transfer of excessive macrophages enhanced oxidative injury and reproduced mechanical allodynia in St2 -/- mice upon tissue incision. Overproduced ROS subsequently activated functionally up-regulated transient receptor potential ankyrin subtype-1 (TRPA1) channel innervating the incisional site to produce mechanical allodynia. Neither deleting St2 nor attenuating ROS affected wound healing of model mice. Conclusions: Our work uncovered a previously unrecognized contribution of IL-33/ST2 signaling in mediating mechanical allodynia and gait impairment of a mouse model of INC pain. Targeting IL-33/ST2 signaling could be a novel therapeutic approach for INC pain management.

WNT2B high­expressed fibroblasts induce the fibrosis of IBD by promoting NK cells secreting IL-33.

Fibrosis is an important pathological change in inflammatory bowel disease (IBD), but the mechanism has yet to be elucidated. WNT2B high­expressed fibroblasts are enriched in IBD intestinal tissues, although the precise function of this group of fibroblasts remains unclear. This study investigated whether WNT2B high­expressed fibroblasts aggravated intestinal tissue damage and fibrosis. Our study provides evidence that WNT2B high­expressed fibroblasts and NK cells were enriched in colitis tissue of patients with IBD. WNT2B high­expressed fibroblasts secreted wnt2b, which bound to FZD4 on NK cells and activated the NF-κB and STAT3 pathways to enhance IL-33 expression. TCF4, a downstream component of the WNT/ß-catenin pathway, bound to p65 and promoted binding to IL-33 promoter. Furthermore, Salinomycin, an inhibitor of the WNT/ß-catenin pathway, inhibited IL-33 secretion in colitis, thereby reducing intestinal inflammation.Knocking down WNT2B reduces NK cell infiltration and IL-33 secretion in colitis, and reduce intestinal inflammation and fibrosis. In conclusion, WNT2B high­expressed fibroblasts activate NK cells by secreting wnt2b, which activates the WNT/ß-catenin and NF-κB pathways to promote IL-33 expression and secretion, potentially culminating in the induction of colonic fibrosis in IBD. KEY MESSAGES: WNT2B high-expressed fibroblasts and NK cells are enriched in colitis tissue, promoting NK cells secreting IL-33. Wnt2b activates NF-κB and STAT3 pathways promotes IL-33 expression by activating p65 and not STAT3. syndrome TCF4 binds to p65 and upregulates the NF- κB pathway. Salinomycin reduces NK cell infiltration and IL-33 secretion in colitis. Knocking down WNT2B mitigates inflammation and fibrosis in chronic colitis.

The IL-33/ST2 Axis Protects Retinal Ganglion Cells by Modulating the Astrocyte Response After Optic Nerve Injury.

IL-33 and its receptor ST2 play crucial roles in tissue repair and homeostasis. However, their involvement in optic neuropathy due to trauma and glaucoma remains unclear. Here, we report that IL-33 and ST2 were highly expressed in the mouse optic nerve and retina. Deletion of IL-33 or ST2 exacerbated retinal ganglion cell (RGC) loss, retinal thinning, and nerve fiber degeneration following optic nerve (ON) injury. This heightened retinal neurodegeneration correlated with increased neurotoxic astrocytes in Il33-/- mice. In vitro, rIL-33 mitigated the neurotoxic astrocyte phenotype and reduced the expression of pro-inflammatory factors, thereby alleviating the RGC death induced by neurotoxic astrocyte-conditioned medium in retinal explants. Exogenous IL-33 treatment improved RGC survival in Il33-/- and WT mice after ON injury, but not in ST2-/- mice. Our findings highlight the role of the IL-33/ST2 axis in modulating reactive astrocyte function and providing neuroprotection for RGCs following ON injury.

Stromal cell and B cell dialogue potentiates IL-33-enriched lymphoid niches to support eosinophil recruitment and function during type 2 immunity.

Eosinophils are involved in host protection against multicellular organisms. However, their recruitment to the mesenteric lymph node (mLN) during type 2 immunity is understudied. Our results demonstrate that eosinophil association with lymphoid stromal niches constructed by fibroblastic reticular cells (FRCs) and lymphatic endothelial cells is diminished in mice selectively lacking interleukin (IL)-4Rα or lymphotoxin-ß (LTß) expression on B cells. Furthermore, eosinophil survival, activation, and enhanced Il1rl1 receptor expression are driven by stromal cell and B cell dialogue. The ligation of lymphotoxin-ß receptor (LTßR) on FRCs improves eosinophil survival and significantly augments IL-33 expression and eosinophil homing to the mLN, thus confirming the significance of lymphotoxin signaling for granulocyte recruitment. Eosinophil-deficient ΔdblGATA-1 mice show diminished mLN expansion, reduced interfollicular region (IFR) alarmin expression, and delayed helminth clearance, elucidating their importance in type 2 immunity. These findings provide insight into dialogue between stromal cells and B cells, which govern mLN eosinophilia, and the relevance of these mechanisms during type 2 immunity.

Population pharmacokinetic/target engagement modelling of tozorakimab in healthy volunteers and patients with chronic obstructive pulmonary disease.

AIMS: This study describes the pharmacokinetic (PK)/target engagement (TE) relationship of tozorakimab, an anti-interleukin (IL)-33 antibody, by building a mechanistic population PK/TE model using phase 1 biomarker data. METHODS: The analysis included tozorakimab PK and TE in serum assessed in 60 tozorakimab-treated participants, including healthy adults and patients with mild chronic obstructive pulmonary disease. Scenarios evaluated three dose frequencies (once every 2, 4 or 6 weeks) administered subcutaneously at seven doses of tozorakimab (30, 60, 90, 120, 150, 300 or 600 mg). For each dose, simulations were performed with 5000 virtual individuals to predict systemic TE. Inhibition of IL-33/soluble ST2 (sST2) complex levels at trough PK at steady state was assessed in each dosing scenario. The PK/TE modelling analyses were performed using a nonlinear mixed-effect modelling approach. RESULTS: The final two-compartment PK model with tozorakimab binding IL-33 in the central compartment adequately described the systemic PK and TE of tozorakimab at population and individual levels. The mean PK parameter estimates of absorption rate, central volume of distribution and clearance were 0.48 (90% confidence interval [CI]: 0.40-0.59, 1/day), 12.64 (90% CI: 8.60-18.62, L) and 0.87 (90% CI: 0.65-1.16, L/day), respectively. Consistent with the observed value, tozorakimab bioavailability was 45%. For all three dose frequencies, predicted inhibition of systemic IL-33/sST2 levels was more than 95% at doses greater than 90 mg. CONCLUSIONS: The PK/TE model reliably quantified the relationship between PK and systemic TE of tozorakimab, with potential utility for predicting clinical dose-response relationships and supporting clinical dose selection.

Circulating interleukin-33 levels in obesity and type 2 diabetes: A systematic review and meta-analysis.

Obesity and type 2 diabetes (T2D) are increasingly prevalent worldwide, and there is a critical need for novel interventions. Interleukin-33 (IL-33), an anti-inflammatory cytokine that regulates metabolism, is a promising biomarker for these conditions. The goal of this systematic review and meta-analysis is to examine the role of IL-33 in obesity and T2D, assessing its potential in predicting disease progression. A systematic search was performed on Scopus, Web of Science, and PubMed up until 30 May 2023. Each study was assessed for quality and sources of bias using the relevant critical appraisal checklists. Meta-analyses were conducted to compare IL-33 levels in individuals with obesity and T2D versus healthy controls (HC), and in obesity alone versus HC. Eighteen studies were included in the systematic review, and nine qualified for meta-analyses. The analyses showed insufficient evidence to suggest a significant difference in IL-33 levels between individuals with T2D and HC (MD = -79.95, 95% CI [-241.38;81.48]), with substantial heterogeneity across the studies observed (I 2 = 97.1%, Tau 2 =33549.15). Similarly, there was insufficient evidence to suggest a significant difference between non-diabetic individuals with obesity and HC (MD = -7.31, 95% CI [-25.74; 11.13]), and heterogeneity was noted (I2 = 86.2%, Tau2 = 342.45). There is insufficient evidence to indicate significant differences in IL-33 levels in individuals with T2D or obesity compared to HC. The results suggest a need for improved IL-33 measurement methods to reduce heterogeneity, enhancing understanding of the role of IL-33 in obesity and T2D, and informing future research and therapeutic strategies.

IL-33 released during challenge phase regulates allergic asthma in an age-dependent way.

Epithelial-derived cytokines, especially type 2 alarmins (TSLP, IL-25, and IL-33), have emerged as critical mediators of type 2 inflammation. IL-33 attracts more interest for its strong association with allergic asthma, especially in childhood asthma. However, the age-dependent role of IL-33 to the development of allergic asthma remains elusive. Here, using OVA-induced allergic asthma model in neonatal and adult mice, we report that IL-33 is the most important alarmin in neonatal lung both at steady state or inflammation. The deficiency of IL-33/ST2 abrogated the development of allergic asthma only in neonates, whereas in adults the effect was limited. Interestingly, the deficiency of IL-33/ST2 equally dampened the ILC2 responses in both neonatal and adult models. However, the effect of IL-33/ST2 deficiency on Th2 responses is age-dependent, which is only blocked in neonates. Furthermore, IL-33/ST2 signaling is dispensable for OVA sensitization. Following OVA challenge in adults, the deficiency of IL-33/ST2 results in compensational more TSLP, which in turn recruits and activates lung DCs and boosts Th2 responses. The enriched γδ T17 cells in IL-33/ST2 deficient neonatal lung suppress the expression of type 2 alarmins, CCL20 and GM-CSF via IL-17A, thus might confer the inhibition of allergic asthma. Finally, on the basis of IL-33 deficiency, the additive protective effects of TSLP blocking is much more pronounced than IL-25 blocking in adults. Our studies demonstrate that the role of IL-33 for ILC2 and Th2 responses varies among ages in OVA models and indicate that the factor of age should be considered for intervention of asthma.

Mast cells contribute to T-cell accumulation in the bronchoalveolar space in mice with IL-33-induced airway inflammation.

Interleukin (IL)-33 released from airway epithelial cells plays a vital role in shaping type 2 immune responses by binding to the ST2 receptor present in many immune cells, including mast cells (MCs). Intranasal administration of IL-33 in mice induces type 2 lung inflammation, an increase in lung MC progenitors, and transepithelial migration of leukocytes to the bronchoalveolar space. The aim of this study was to determine the contribution of MCs in IL-33-induced lung pathology. Four daily intranasal administrations of IL-33 reduced spirometry-like lung function parameters, induced airway hyperresponsiveness, and increased leukocytes in bronchoalveolar lavage fluid (BAL) in an ST2-dependent manner. MC-deficient (Cpa3cre/+) mice, which lack MCs, had intact spirometry-like lung function but slightly reduced airway hyperresponsiveness, possibly related to reduced IL-33 or serotonin. Strikingly, Cpa3cre/+ mice exposed to IL-33 had 50% reduction in BAL T-cells, and CXCL1 and IL-33 were reduced in the lung. Intranasal IL-33 induced CXCR2 expression in T-cells in a MC-independent fashion. Furthermore, IL-33-induced lung MCs were immunopositive for CXCL1 and localized in the epithelium of wild-type mice. These results suggest that MCs are required to sustain intact lung IL-33 and CXCL1 levels in mice with IL-33-induced airway inflammation, thereby facilitating T-cell accumulation in the bronchoalveolar space.

Overexpression of the ß-Subunit of Acid Ceramidase in the Epidermis of Mice Provokes Atopic Dermatitis-like Skin Symptoms.

We previously reported that a pathogenic abnormality in the barrier and water-holding functions of the stratum corneum (SC) in the skin of patients with atopic dermatitis (AD) is mainly attributable to significantly decreased levels of total ceramides in the SC. That decrease is mediated by the abnormal expression of a novel ceramide-reducing enzyme, sphingomyelin/glucosylceramide deacylase (SGDase), which is the ß-subunit (ASAH1b) of acid ceramidase. In this study, we determined whether mice overexpressing ASAH1b in their epidermis develop AD-like skin symptoms. We generated transgenic (TG) mice overexpressing ASAH1b, regulated by the involucrin promoter, to localize its expression in the upper epidermis. After hair removal using a depilatory cream containing glycolic acid, the TG mice without any visible skin inflammation at 8 weeks of age had increased levels of ASAH1b and decreased levels of SC ceramide, with disrupted barrier functions measured by trans-epidermal water loss compared to the wild-type (WT) mice. Interestingly, enzymatic assays revealed that SGDase activity was not detectable in the skin of the TG mice compared to WT mice. Immunological staining revealed that there was an increased expression level of IL-33 in the epidermis and an accumulation of macrophages in the dermis of TG mice compared to WT mice, which are phenotypic characteristics of AD, that were exacerbated by tape-stripping of the skin. In the skin of the TG mice, the mRNA levels of IL-5, CCL11, IL-22, CXCL10, and IFNγ were significantly upregulated compared to the WT mice, and tape-stripping significantly increased the mRNA levels of IL-4, IL-33, CXCL1, CXCL12, TLR9, and CD163 compared to WT mice. These findings strongly indicate that the skin of the depilatory cream-treated TG mice exists in an atopic dry skin condition that is highly sensitive to various environmental stimuli. The sum of our results suggests that ASAH1b itself, even in the absence of its enzymatic activity, is a major etiologic factor for atopic dry skin symptoms via an unknown mechanism.

Exploratory pharmacodynamics and efficacy of PF-06817024 in a Phase 1 study of patients with chronic rhinosinusitis and atopic dermatitis.

PF-06817024 is a humanized antibody against interleukin-33 that has the potential to inhibit type 2 inflammation. An exploratory analysis of the pharmacodynamics and clinical effects of single and repeat doses of PF-06817024 was assessed in patients with chronic rhinosinusitis with nasal polyps (CRSwNP) and patients with moderate-to-severe atopic dermatitis (AD), respectively, as part of a Phase 1, first-in-human study. Rhinosinusitis symptoms were improved, and nasal polyps were decreased in size following treatment with PF-06817024 in patients with CRSwNP. In patients with AD, PF-06817024, in aggregate, reduced disease severity and improved symptoms, as demonstrated by greater percentage decrease from baseline in Eczema Area and Severity Index (EASI) scores and reduced pruritus numerical rating scores, compared with placebo. The efficacy in AD appeared to be bimodal with a sub-group of participants exhibiting high levels of improvement (EASI75 and EASI90) for a sustained period of time after dosing. In patients with CRSwNP, a consistent trend of decrease in eosinophil levels was observed in the PF-06817024 group, compared with placebo. Further research would be needed to confirm the clinical benefit and safety of PF-06817024 as a treatment for allergic diseases. Trial registration ClinicalTrials.gov, NCT02743871. Registered 15 April 2016, https://clinicaltrials.gov/study/NCT02743871?term=NCT02743871&rank=1 .

Transcriptional profiling identifies IL-33-expressing intestinal stromal cells as a signaling hub poised to interact with enteric neurons.

Recent advancements in mucosal immunology have unveiled a complex network of intercellular connections within diverse tissues, shedding light on the unique properties of different cell types. Central to this intricate network is the cytokine IL-33, which has gained significant attention for its critical role in various diseases, from allergy to cancer, triggering type 2 immune responses, among others. Recent research has challenged the prior assumptions attributing IL-33 expression to epithelial cells, highlighting stromal cells as the predominant source in adipose tissue and the lungs. However, in the complex landscape of the intestine, where IL-33 plays a crucial role in mediating immune surveillance and tolerance and is implicated in many gut-related disorders, its primary source, regulation, and main characteristics need more exploration. This study identifies stromal cells as the primary IL-33-expressing cell type in the small intestine. By investigating their transcriptome and intrinsic signaling pathways, we have uncovered a possible role of IL-33+ stromal cells in maintaining the stem cell niche and their potential crosstalk with neurons relevant to the regulation of axonogenesis. Importantly, our experiments have demonstrated that vasoactive intestinal peptide stimulation of a primary intestinal stromal cell culture significantly amplifies IL-33 expression on mRNA and protein level. Therefore, our study represents a significant leap forward in understanding the plethora of interactions IL-33+ intestinal stromal cells maintain in the intestine, paving the way for future investigations into stromal-neuro crosstalk in the gut. These findings hold great promise for developing targeted therapeutic strategies aimed at harnessing the potential of IL-33 across a spectrum of diseases.

IL-1 Family Blockade in Cytokine Storm Syndromes.

Interleukin-1 is a prototypic proinflammatory cytokine that is elevated in cytokine storm syndromes (CSSs), such as secondary hemophagocytic lymphohistiocytosis (sHLH) and macrophage activation syndrome (MAS). IL-1 has many pleotropic and redundant roles in both innate and adaptive immune responses. Blockade of IL-1 with recombinant human interleukin-1 receptor antagonist has shown efficacy in treating CSS. Recently, an IL-1 family member, IL-18, has been demonstrated to be contributory to CSS in autoinflammatory conditions, such as in inflammasomopathies (e.g., NLRC4 mutations). Anecdotally, recombinant IL-18 binding protein can be of benefit in treating IL-18-driven CSS. Lastly, another IL-1 family member, IL-33, has been postulated to contribute to CSS in an animal model of disease. Targeting of IL-1 and related cytokines holds promise in treating a variety of CSS.