Skin uses interdependent cellular networks for barrier integrity and host immunity, but most underlying mechanisms remain obscure. Herein, we demonstrate that the human parasitic helminth Schistosoma mansoni inhibited pruritus evoked by itch-sensing afferents bearing the Mas-related G-protein-coupled receptor A3 (MrgprA3) in mice. MrgprA3 neurons controlled interleukin (IL)-17+ γδ T cell expansion, epidermal hyperplasia and host resistance against S. mansoni through shaping cytokine expression in cutaneous antigen-presenting cells. MrgprA3 neuron activation downregulated IL-33 but induced IL-1β and tumor necrosis factor in macrophages and type 2 conventional dendritic cells partially through the neuropeptide calcitonin gene-related peptide. Macrophages exposed to MrgprA3-derived secretions or bearing cell-intrinsic IL-33 deletion showed increased chromatin accessibility at multiple inflammatory cytokine loci, promoting IL-17/IL-23-dependent changes to the epidermis and anti-helminth resistance. This study reveals a previously unrecognized intercellular communication mechanism wherein itch-inducing MrgprA3 neurons initiate host immunity against skin-invasive parasites by directing cytokine expression patterns in myeloid antigen-presenting cell subsets.

• MeSH
• dendritické buňky imunologie   MeSH
• interleukin 33 * metabolismus   imunologie   MeSH
• kůže imunologie   parazitologie   MeSH
• lidé MeSH
• makrofágy imunologie   metabolismus   MeSH
• myeloidní buňky imunologie   metabolismus   MeSH
• myši inbrední C57BL MeSH
• myši knockoutované MeSH
• myši MeSH
• neurony imunologie   metabolismus   MeSH
• pruritus imunologie   MeSH
• receptory spřažené s G-proteiny * metabolismus   imunologie   genetika   MeSH
• Schistosoma mansoni * imunologie   MeSH
• schistosomiasis mansoni * imunologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

In the past decade, single-cell transcriptomics has helped to uncover new cell types and states and led to the construction of a cellular compendium of health and disease. Despite this progress, some difficult-to-sequence cells remain absent from tissue atlases. Eosinophils-elusive granulocytes that are implicated in a plethora of human pathologies1-5-are among these uncharted cell types. The heterogeneity of eosinophils and the gene programs that underpin their pleiotropic functions remain poorly understood. Here we provide a comprehensive single-cell transcriptomic profiling of mouse eosinophils. We identify an active and a basal population of intestinal eosinophils, which differ in their transcriptome, surface proteome and spatial localization. By means of a genome-wide CRISPR inhibition screen and functional assays, we reveal a mechanism by which interleukin-33 (IL-33) and interferon-γ (IFNγ) induce the accumulation of active eosinophils in the inflamed colon. Active eosinophils are endowed with bactericidal and T cell regulatory activity, and express the co-stimulatory molecules CD80 and PD-L1. Notably, active eosinophils are enriched in the lamina propria of a small cohort of patients with inflammatory bowel disease, and are closely associated with CD4+ T cells. Our findings provide insights into the biology of eosinophils and highlight the crucial contribution of this cell type to intestinal homeostasis, immune regulation and host defence. Furthermore, we lay a framework for the characterization of eosinophils in human gastrointestinal diseases.

• MeSH
• analýza genové exprese jednotlivých buněk MeSH
• antigeny CD80 metabolismus   MeSH
• eozinofily * klasifikace   cytologie   imunologie   metabolismus   MeSH
• idiopatické střevní záněty imunologie   MeSH
• imunita * MeSH
• interferon gama MeSH
• interleukin 33 MeSH
• kolitida * imunologie   patologie   MeSH
• lidé MeSH
• myši MeSH
• proteom MeSH
• střeva * imunologie   patologie   MeSH
• T-lymfocyty MeSH
• transkriptom MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Aim: Overactivation of the IL-33/IL-13 axis is the main step in initializing allergic inflammation and promoting allergic diseases. Data on viral pathogens as risk factors for subsequent allergic disease are contradictory. The strongest associations have been made between upper respiratory tract virus infections and asthma. Intestinal viral infections also activate IL-33 and IL-13 as part of the innate antiviral response. The aim of this study was to test whether there are differences in IL-13 and IL-33 concentrations in pediatric patients with acute rotavirus- and norovirus infections and healthy controls. Material and Methods: Forty children with acute rotavirus, 27 with acute norovirus intestinal infections and 17 control children were enrolled in this study. Blood IL-33 and IL-13 detection was performed with enzyme-linked immunosorbent assays (ELISAs). Results: Acute rotavirus infection caused a significant elevation in IL-33 and IL-13 compared to acute norovirus infection (63.85 pg/ml vs. 0, P = 0.0026, and 94.24 pg/ml vs. 0.88 pg/ml, P = 0.0003, respectively) and healthy controls (63.85 pg/ml vs. 9.89 pg/ ml, P = 0.0018, and 94.24 pg/ml vs. 0.14 pg/ml, P < 0.0001, respectively). There was no significant difference in IL-33 and IL-13 concentrations between the acute norovirus group and healthy controls (0 vs. 9.89 pg/ml, P = 0.8276 and 0.88 pg/ml vs. 0.14 pg/ml, P = 0.1652, respectively). Conclusion: Acute rotavirus infection causes a significant elevation in IL-33 and IL-13, compared to norovirus and healthy control children.

• MeSH
• dítě MeSH
• feces MeSH
• gastroenteritida diagnóza   MeSH
• infekce viry z čeledi Caliciviridae * diagnóza   MeSH
• interleukin 33 MeSH
• interleukin-13 MeSH
• klinická studie jako téma MeSH
• lidé MeSH
• Norovirus MeSH
• rotavirové infekce * diagnóza   MeSH
• Rotavirus MeSH
• Check Tag
• dítě MeSH
• lidé MeSH

BACKGROUND: Monoclonal antibodies targeting IgE, interleukin-4 and -13, and interleukin-5 are effective in treating severe type 2 asthma, but new targets are needed. Itepekimab is a new monoclonal antibody against the upstream alarmin interleukin-33. The efficacy and safety of itepekimab as monotherapy, as well as in combination with dupilumab, in patients with asthma are unclear. METHODS: In a phase 2 trial, we randomly assigned, in a 1:1:1:1 ratio, adults with moderate-to-severe asthma receiving inhaled glucocorticoids plus long-acting beta-agonists (LABAs) to receive subcutaneous itepekimab (at a dose of 300 mg), itepekimab plus dupilumab (both at 300 mg; combination therapy), dupilumab (300 mg), or placebo every 2 weeks for 12 weeks. After randomization, LABA was discontinued at week 4, and inhaled glucocorticoids were tapered over weeks 6 through 9. The primary end point was an event indicating a loss of asthma control, assessed in the itepekimab group and the combination group, as compared with the placebo group. Secondary and other end points included lung function, asthma control, quality of life, type 2 biomarkers, and safety. RESULTS: A total of 296 patients underwent randomization. By 12 weeks, an event indicating a loss of asthma control occurred in 22% of the patients in the itepekimab group, 27% of those in the combination group, and 19% of those in the dupilumab group, as compared with 41% of those in the placebo group; the corresponding odds ratios as compared with placebo were as follows: in the itepekimab group, 0.42 (95% confidence interval [CI], 0.20 to 0.88; P = 0.02); in the combination group, 0.52 (95% CI, 0.26 to 1.06; P = 0.07); and in the dupilumab group, 0.33 (95% CI, 0.15 to 0.70). As compared with placebo, the forced expiratory volume in 1 second before bronchodilator use increased with the itepekimab and dupilumab monotherapies but not with the combination therapy. Itepekimab treatment improved asthma control and quality of life, as compared with placebo, and led to a greater reduction in the mean blood eosinophil count. The incidence of adverse events was similar in all four trial groups. CONCLUSIONS: Interleukin-33 blockade with itepekimab led to a lower incidence of events indicating a loss of asthma control than placebo and improved lung function in patients with moderate-to-severe asthma. (Funded by Sanofi and Regeneron Pharmaceuticals; ClinicalTrials.gov number, NCT03387852.).

• MeSH
• antiastmatika škodlivé účinky   terapeutické užití   MeSH
• bronchiální astma farmakoterapie   MeSH
• dospělí MeSH
• dvojitá slepá metoda MeSH
• glukokortikoidy terapeutické užití   MeSH
• humanizované monoklonální protilátky terapeutické užití   MeSH
• injekce subkutánní MeSH
• interleukin 33 antagonisté a inhibitory   MeSH
• kombinovaná farmakoterapie MeSH
• kvalita života MeSH
• lidé středního věku MeSH
• lidé MeSH
• neúspěšná terapie MeSH
• receptory interleukinu-4 antagonisté a inhibitory   MeSH
• senioři MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze II MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH

The molecular basis for the propensity of a small number of environmental proteins to provoke allergic responses is largely unknown. Herein, we report that mite group 13 allergens of the fatty acid-binding protein (FABP) family are sensed by an evolutionarily conserved acute-phase protein, serum amyloid A1 (SAA1), that promotes pulmonary type 2 immunity. Mechanistically, SAA1 interacted directly with allergenic mite FABPs (Der p 13 and Blo t 13). The interaction between mite FABPs and SAA1 activated the SAA1-binding receptor, formyl peptide receptor 2 (FPR2), which drove the epithelial release of the type-2-promoting cytokine interleukin (IL)-33 in a SAA1-dependent manner. Importantly, the SAA1-FPR2-IL-33 axis was upregulated in nasal epithelial cells from patients with chronic rhinosinusitis. These findings identify an unrecognized role for SAA1 as a soluble pattern recognition receptor for conserved FABPs found in common mite allergens that initiate type 2 immunity at mucosal surfaces.

• MeSH
• alergeny imunologie   MeSH
• alergická rýma imunologie   patologie   MeSH
• antigeny roztočů domácího prachu imunologie   MeSH
• bronchiální astma imunologie   patologie   MeSH
• dospělí MeSH
• epitelové buňky MeSH
• humorální imunita MeSH
• interleukin 33 metabolismus   MeSH
• kultivované buňky MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• modely nemocí na zvířatech MeSH
• myši knockoutované MeSH
• myši MeSH
• plíce cytologie   imunologie   patologie   MeSH
• primární buněčná kultura MeSH
• přirozená imunita MeSH
• proteiny vázající mastné kyseliny imunologie   MeSH
• receptory lipoxinů metabolismus   MeSH
• receptory pro formylované peptidy metabolismus   MeSH
• respirační sliznice imunologie   metabolismus   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• sérový amyloid A genetika   metabolismus   MeSH
• signální transdukce imunologie   MeSH
• upregulace MeSH
• zvířata MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• myši MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

Background: Psoriasis vulgaris is a chronic autoimmune disease associated with systemic inflammation. Increased levels of numerous cytokines, chemokines, growth factors, and other molecules were found in the skin and in the circulation of psoriatic patients. Alarmins, also known as danger signals, are intracellular proteins, which are released to an extracellular space after infection or damage. They are the markers of cell destructive processes. Objective: The aim of the present study was to evaluate the suitability of selected alarmins (HMGB1, IL-33, S100A7, and S100A12) as potential biomarkers of severity of psoriasis and to explore possible relationships between these proteins for the purpose of better understanding their roles in the immunopathology of psoriasis. Methods: The serum levels of selected alarmins were measured in 63 psoriatic patients and 95 control individuals. The levels were assessed by the ELISA technique using commercial kits. The data were statistically processed with MedCalc version 19.0.5. Results: In psoriatic patients, we found significantly increased levels of HMGB1 (p < 0.05), IL-33 (p < 0.01), S100A7 (p < 0.0001), and S100A12 (p < 0.0001). In addition, we found a significant relationship between HMGB1 and S100A7 (Spearman's rho = 0.276, p < 0.05) in the patients and significant relationship between HMGB1 and IL-33 in the controls (Spearman's rho = 0.416, p < 0.05). We did not find any relationship between observed alarmins and the disease severity. Conclusions: The alarmins HMGB1, IL-33, S100A7, and S100A12 were significantly elevated in the serum of patients, which states the hypothesis that they play specific roles in the immunopathology of psoriasis. However, we have not yet found a relationship between observed alarmins and the disease severity. The discovery of the relationship between HMGB1 and S100A7 is a novelty that should be studied in the future to further clarify its role and importance.

• MeSH
• alarminy krev   MeSH
• dospělí MeSH
• interleukin 33 krev   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• protein HMGB1 krev   MeSH
• protein S100A12 krev   MeSH
• protein S100A7 krev   MeSH
• psoriáza imunologie   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• stupeň závažnosti nemoci MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

We find that cardiac group 2 innate lymphoid cells (ILC2s) are essential for the development of IL-33-induced eosinophilic pericarditis. We show a pathogenic role for ILC2s in cardiac inflammation, in which ILC2s activated by IL-33 drive the development of eosinophilic pericarditis in collaboration with cardiac fibroblasts. ILCs, not T and B cells, are required for the development of pericarditis. ILC2s transferred to the heart of Rag2-/-Il2rg-/- mice restore their susceptibility to eosinophil infiltration. Moreover, ILC2s direct cardiac fibroblasts to produce eotaxin-1. We also find that eosinophils reside in the mediastinal cavity and that eosinophils transferred to the mediastinal cavity of eosinophil-deficient ΔdblGATA1 mice following IL-33 treatment migrate to the heart. Thus, the serous cavities may serve as a reservoir of cardiac-infiltrating eosinophils. In humans, patients with pericarditis show higher amounts of ILCs in pericardial fluid than do healthy controls and patients with other cardiac diseases. We demonstrate that ILCs play a critical role in pericarditis.

• MeSH
• chemokin CCL11 genetika   metabolismus   MeSH
• eozinofily účinky léků   patologie   MeSH
• fibroblasty účinky léků   metabolismus   MeSH
• funkční vyšetření srdce účinky léků   MeSH
• interleukin 33 farmakologie   MeSH
• interleukin-1 receptor-like 1 protein nedostatek   metabolismus   MeSH
• interleukin-5 metabolismus   MeSH
• lidé MeSH
• lymfocyty účinky léků   imunologie   MeSH
• mediastinum patologie   MeSH
• myši inbrední BALB C MeSH
• náchylnost k nemoci MeSH
• perikarditida genetika   imunologie   patofyziologie   MeSH
• pohyb buněk účinky léků   MeSH
• přirozená imunita * účinky léků   MeSH
• regulace genové exprese účinky léků   MeSH
• signální transdukce účinky léků   MeSH
• srdce účinky léků   patofyziologie   MeSH
• upregulace účinky léků   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

The epidermis is the external layer of the skin and is composed mainly of keratinocytes. Therefore, keratinocytes play an indispensable role as inherent constituents of the skin barrier in physical defenses against environmental threats. Keratinocytes also exert an active protective role against invasion by pathogens. This competency is of particular importance when physical defenses fail as a consequence of skin injury. During the inflammatory phase of healing, keratinocytes act as immuno-modulators, managing inflammation via a rigorously coordinated network of inflammatory cascades, triggered by keratinocyte-receptor communication with the surroundings in a paracrine and autocrine manner. This review summarizes current understandings of the coordinated inflammatory network and focuses on recent progress regarding the role of keratinocytes in early phases of skin wound healing.

• MeSH
• cytokiny MeSH
• fyziologie kůže MeSH
• hojení ran fyziologie   MeSH
• interleukin 33 MeSH
• interleukin-1alfa MeSH
• interleukin-1beta MeSH
• keratinocyty * fyziologie   MeSH
• kůže * zranění   MeSH
• lidé MeSH
• mediátory zánětu fyziologie   MeSH
• NF-kappa B MeSH
• protein NLRP3 MeSH
• toll-like receptory MeSH
• zánět * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• práce podpořená grantem MeSH
• přehledy MeSH

Atherosclerosis has been recognized as an inflammatory/autoimmune disease. The long-standing low-grade inflammation which fuels its development is primarily focused on the components of the vessel wall. Originally, inflammation in atherogenesis was supposed to be driven by the pro-inflammatory Th1 cellular and cytokine immune response. On the basis of accumulating evidence, this view has been re-evaluated to include the Th17/Th1 axis which is shared by most diseases of sterile inflammation. The anti-inflammatory Th2 cellular and cytokine immune response is initiated concomitantly with the former two, the latter dampening their harmful reactions which culminate in full-blown atherosclerosis. Interleukin-33, a novel member of the IL-1 cytokine superfamily, was suggested to take part in the anti-atherogenic response by mediating the Th1-to-Th2 switch of the immune reactions. However, IL-33 is a multifaceted mediator with both pro- and anti-inflammatory activities, also called a "dual factor" or a "Janus face" interleukin. IL-33 occurs both in an extracellular (cytokine-like) and in a nuclear-bound (transcription factor-like) form, each of them performing distinct activities of their own. This review article presents the latest data relevant to IL-33's role in atherosclerosis and cardiac diseases as perceived by a cardiologist and a cardiac surgeon.

• MeSH
• ateroskleróza imunologie   patologie   MeSH
• buňky Th17 imunologie   patologie   MeSH
• interleukin 33 imunologie   MeSH
• lidé MeSH
• srdeční selhání imunologie   patologie   MeSH
• Th1 buňky imunologie   patologie   MeSH
• Th2 buňky imunologie   patologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

OBJECTIVE: ST2, a member of the interleukin-1 receptor family, is selectively expressed on Th2 cells and mediates important Th2 functions. IL-33 is a specific ligand of ST2. The aim of the study was to determine whether serum levels of soluble ST2 (sST2) or IL-33 predict activity of the disease in patients with ANCA-associated vasculitides (AAV). METHODS: 139 AAV patients and 62 controls were studied. IL-33 and sST2 in the blood were measured with a commercially available ELISA. RESULTS: Newly diagnosed AAV patients had higher sST2 levels than controls (P < 0.01). Levels of sST2 were significantly higher in active newly diagnosed AAV patients than in patients with remission (P < 0.001). IL-33 levels were higher in AAV patients than in the control groups (P = 0.002). However, serum IL-33 levels were not increased in patients with active AAV compared to patients in remission. IL-33 levels were higher in patients with granulomatosis with polyangiitis than in patients with microscopic polyangiitis (P = 0.012). CONCLUSIONS: Serum sST2, but not serum IL-33, may be a marker of activity in AAV patients.

• MeSH
• ANCA-asociované vaskulitidy imunologie   MeSH
• dospělí MeSH
• interleukin 33 krev   MeSH
• lidé středního věku MeSH
• lidé MeSH
• receptory buněčného povrchu krev   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH