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Herpes simplex virus-1 (HSV-1) is common and can cause significant disease in humans. Unfortunately, efforts to develop effective vaccines against HSV-1 have so far failed. A detailed understanding of how the virus infects its host and how the host mounts potent immune responses against the virus may inform new vaccine approaches. Here, using a zosteriform mouse model, we examined how the HSV-1 gene UL56 affects the ability of the virus to cause morbidity and generate protective immunity. A UL56 deletion mutant, ΔUL56, was derived from the wild-type HSV-1 strain SC16, alongside a revertant strain in which UL56 was reintroduced in ΔUL56. In vitro, the three virus strains replicated in a similar manner; however, in vivo, only the wild type and the revertant strains caused shingles-like skin lesions and death. Mice previously infected with ΔUL56 became resistant to a lethal challenge with the wild-type SC16. The protective immunity induced by ΔUL56 was independent of IL-1, IL-33, and IL-36 signaling through IL-1RAP. Both skin and intramuscular ΔUL56 inoculation generated protective immunity against a lethal SC16 challenge. After 6 months, female mice remained resistant to infection, while male mice exhibited signs of declining protection. Our data demonstrate that UL56 is important for the ability of HSV-1 to spread within the infected host and that a ∆UL56 strain elicits an effective immune response against HSV-1 despite this loss of virulence. These findings may guide further HSV-1 vaccine development. [ABSTRACT FROM AUTHOR]

Objectives: Generalized pustular psoriasis (GPP) is a rare, life-threatening skin inflammatory disorder. This study aimed to describe the disease course, treatment strategies, and healthcare utilization among patients with GPP in Portugal. Methods: This multicentric, observational, retrospective study included consecutive adult patients with GPP undergoing a dermatology evaluation in different reporting institutions by experienced dermatologists between 2002 and 2023. Results: A total of 59 patients were assessed. Most of the cohort had a previous history of plaque psoriasis (71%) and 83% presented at least one comorbidity. At the initial encounter, 64% of the cohort needed hospitalization. Systemic involvement was common, including fever (37%), and elevated white blood cell count and erythrocyte sedimentation rate/C-reactive protein (49%). Nearly, 73% of patients initiated systemic drugs, and 70% had to discontinue the first treatment. During the study, 98% of patients experienced at least one flare. At the last visit, 3.4% of patients had died, and 71.2% exhibited signs of active disease despite undergoing treatment. Conclusions: Our study demonstrates that GPP is a chronic, debilitating condition associated with systemic involvement, frequent flares, and hospitalizations, despite receiving multiple systemic treatments. Improved disease awareness and new treatments are needed to improve patient care and decrease the burden of the disease. [ABSTRACT FROM AUTHOR]

Yuan Xu, Jing-Yan Wang, Yang Zou, Xue-Wei Ma, Tian Meng College of Health Industry, Sichuan Tourism University, Chengdu, Sichuan, 610100, People’s Republic of ChinaCorrespondence: Yuan Xu, Email 230973159@qq.comAbstract: Inflammatory cytokines, interleukin-36 (IL-36), IL-37, IL-38 belong to IL-1 family. The IL-36 subfamily obtains pro- and anti-inflammatory effects on various immune responses. Cytokine IL-37, has anti-inflammatory functions in immunity, and the recently identified IL-38 negatively associated with disease pathogenesis. To date, expression of IL-36, IL-37, IL-38 is reported dysregulated in osteoarthritis (OA) and rheumatoid arthritis (RA), and may be disease markers for arthritis-related diseases. Interestingly, expression of IL-38 was different either in OA patients or animal models, and expression of IL-36Ra in synovium was different in OA and RA patients. Moreover, functional studies have demonstrated significant role of these cytokines in OA and RA progress. These processes were related to immune cells and non-immune cells, where the cytokines IL-36, IL-37, IL-38 may regulate downstream signalings in the cells, and then involve in OA, RA development. In this review, we comprehensively discuss recent advancements in cytokines and the development of OA, RA. We hope that targeting these cytokines will become a potential treatment option for OA and RA in the future.Keywords: IL-36, IL-37, IL-38, osteoarthritis, rheumatoid arthritis

This review explores the intricate relationship between generalized pustular psoriasis (GPP) and various systemic diseases, shedding light on the broader impacts of this severe skin condition beyond its primary dermatological manifestations. GPP is identified as not only a profound contributor to skin pathology but also a significant risk factor for systemic diseases affecting cardiovascular, hepatic, renal, pulmonary, and skeletal systems, as well as associated with an increased incidence of anemia, depression, anxiety, and arthritis. The research highlights the complex interplay of cytokines, particularly IL-17 and IL-36, which are central to the pathophysiology of GPP and implicated in the exacerbation of systemic conditions. Key findings indicate a higher incidence of cardiovascular events in GPP patients compared to those with other severe forms of psoriasis, notably with a stronger correlation between myocardial infarction history and GPP development. Liver disturbances, frequently reversible upon psoriasis remission, suggest a cytokine-mediated link to hepatic health. Renal dysfunction appears elevated in GPP sufferers, with IL-17 and IL-36 potentially driving renal fibrosis. Similarly, interstitial lung disease and osteoporosis in GPP patients underscore the systemic reach of inflammatory processes initiated in the skin. The associations with anemia, depression, anxiety, and arthritis further complicate the clinical management of GPP, requiring a multidisciplinary approach. The study concludes that managing GPP effectively requires a holistic approach that addresses both the cutaneous and systemic dimensions of the disease, advocating for continued research into the mechanisms that connect GPP with broader health implications to refine therapeutic strategies. [ABSTRACT FROM AUTHOR]

To study the effects of the anti-IL-23A antibody risankizumab on the IL-36γ/IL-23A/IL-17A signalling cascade we used a newly developed 3D skin model consisting of primary human keratinocytes, fibroblasts and γδ-T-cells. In this in vitro study we developed new full-thickness 3D skin models containing normal human epidermal keratinocytes (NHEK), normal human dermal fibroblasts (NHDF) and IL-23A responsive and IL-17A producing γδ-T-cells. The effects of IL-36γ stimulation with and without risankizumab treatment on IL-23A and IL-17A expression were examined at the RNA and protein levels. In preliminary monolayer experiments stimulation of γδ-T-cells with IL-23A promoted the IL-17A expression that was inhibited after risankizumab treatment. Using 3D skin models containing γδ-T-cells, we found that stimulation with IL-36γ significantly increased not only IL-23A but also IL-17A expression. These effects were inhibited by concomitant treatment with risankizumab. Our results showed that blockade of IL-23A has inhibitory effects on the IL-36γ/IL-23A feedforward loop. Our newly developed 3D skin model containing IL-23A responsive and IL-17A producing γδ-T-cells enables molecular analysis of targeted therapies aimed at the IL-36γ/IL-23A/IL-17A signalling cascade in psoriasis. [ABSTRACT FROM AUTHOR]

IL-36 cytokines are emerging as beneficial in immunity against pathogens and cancers but can also be detrimental when dysregulated in autoimmune and autoinflammatory conditions. Interest in targeting IL-36 activity for therapeutic purposes is rapidly growing, yet many unknowns about the functions of these cytokines remain. Thus, the availability of robust research tools is essential for both fundamental basic science and pre-clinical studies to fully access outcomes of any manipulation of the system. For this purpose, a floxed Il1rl2, the gene encoding the IL-36 receptor, mouse strain was developed to facilitate the generation of conditional knockout mice. The targeted locus was engineered to contain an inverted mCherry reporter sequence that upon Cre-mediated recombination will be flipped and expressed under the control of the endogenous Il1rl2 promoter. This feature can be used to confirm knockout in individual cells but also as a reporter to determine which cells express the IL-36 receptor IL-1RL2. The locus was confirmed to function as intended and further used to demonstrate the expression of IL-1RL2 in barrier tissues. Il1rl2 expression was detected in leukocytes in all barrier tissues. Interestingly, strong expression was observed in epithelial cells at locations in direct contact with the environment such as the skin, oral mucosa, the esophagus, and the upper airways, but almost absent from epithelial cells at more inward facing sites, including lung alveoli, the small intestine, and the colon. These findings suggest specialized functions of IL-1RL2 in outward facing epithelial tissues and cells. The generated mouse model should prove valuable in defining such functions and may also facilitate basic and translational research. [ABSTRACT FROM AUTHOR]

Abstract is missing (Short communication)

Abstract Interleukin (IL)-36 family is closely associated with inflammation and consists of IL-36α, IL-36β, IL-36γ, and IL-36Ra. The role of IL-36 in the context of asthma and asthmatic phenotypes is not well characterized. We examined the sputum IL-36 levels in patients with different asthma phenotypes in order to unravel the mechanism of IL-36 in different asthma phenotypes. Our objective was to investigate the induced sputum IL-36α, IL-36β, IL-36γ, and IL-36Ra concentrations in patients with mild asthma, and to analyze the relationship of these markers with lung function and other cytokines in patients with different asthma phenotypes. Induced sputum samples were collected from patients with mild controlled asthma (n = 62, 27 males, age 54.77 ± 15.49) and healthy non-asthmatic controls (n = 16, 10 males, age 54.25 ± 14.60). Inflammatory cell counts in sputum were determined. The concentrations of IL-36 and other cytokines in the sputum supernatant were measured by ELISA and Cytometric Bead Array. This is the first study to report the differential expression of different isoforms of IL-36 in different asthma phenotypes. IL-36α and IL-36β concentrations were significantly higher in the asthma group (P = 0.003 and 0.031), while IL-36Ra concentrations were significantly lower (P

AbstractObjectives Generalized pustular psoriasis (GPP) is a rare, life-threatening skin inflammatory disorder. This study aimed to describe the disease course, treatment strategies, and healthcare utilization among patients with GPP in Portugal.Methods This multicentric, observational, retrospective study included consecutive adult patients with GPP undergoing a dermatology evaluation in different reporting institutions by experienced dermatologists between 2002 and 2023.Results A total of 59 patients were assessed. Most of the cohort had a previous history of plaque psoriasis (71%) and 83% presented at least one comorbidity. At the initial encounter, 64% of the cohort needed hospitalization. Systemic involvement was common, including fever (37%), and elevated white blood cell count and erythrocyte sedimentation rate/C-reactive protein (49%). Nearly, 73% of patients initiated systemic drugs, and 70% had to discontinue the first treatment. During the study, 98% of patients experienced at least one flare. At the last visit, 3.4% of patients had died, and 71.2% exhibited signs of active disease despite undergoing treatment.Conclusions Our study demonstrates that GPP is a chronic, debilitating condition associated with systemic involvement, frequent flares, and hospitalizations, despite receiving multiple systemic treatments. Improved disease awareness and new treatments are needed to improve patient care and decrease the burden of the disease.

Generalized pustular psoriasis (GPP) is a rare chronic inflammatory pustular dermatosis that presents as painful erythema with sterile pustules on nonacral skin. No unified standard and guideline for the treatment of GPP has been established. Several biologics have been tried for GPP, with varying success. Acrodermatitis continua of Hallopeau (ACH) is a very rare disabling variant of pustular psoriasis characterized by sterile pustules on the fingers and toes, including the nail bed. Comparatively, treating ACH is highly challenging due to its commonly therapy-resistant disease course. The pathogenic role of IL-36 signaling axis has been currently identified in GPP development. Spesolimab, the first anti-interleukin-36 receptor biologic, has been approved for treating GPP flares and shown promising results. In view of a shared pathogenesis between GPP and ACH, specolimab may be an effective treatment for ACH. Currently, there is no case and clinical trial data exist on this condition. Therefore, this case was aim to describe real-world experience of spesolimab use in ACH coexisting with GPP. We report an Asian patient with a 16-year-history of GPP and ACH with marked pustulosis on the nail bed and onychodystrophy. He received conventional systemic regimen acitretin, cyclosporine and biologics adalimumab and secukinumab, but experienced relapse for skin lesions and refractory for nail lesions. He was then treated with a single dose of spesolimab in combination with secukinumab, which resulted in skin clearance and nearly complete resolution of nail lesions over a 32-week period. Our observation suggests that spesolimab should be considered for the treatment of ACH, especially in the patients with intractable nail lesions and concomitant GPP. [ABSTRACT FROM AUTHOR]

The immunopathogenesis of HS is partially understood and exhibits features of an autoinflammatory disease; it is associated with the potential involvement of B cells and the contribution of Th1 or Th17 cell subsets. Recently, the pathogenic role of both innate immunity and IL-1 family cytokines in HS has been deeply investigated. Several agents targeting the IL-1 family pathway at different levels are currently available and under investigation for the treatment of HS. HS is still characterized by unmet clinical needs and represents an expanding field in the current scientific research. The aim of this narrative review is to describe the pathological dysregulation of IL-1 family members in HS and to provide an update on therapeutic strategies targeting IL-1 family cytokine signaling. Further clinical and preclinical data may likely lead to the enrichment of the therapeutic armamentarium of HS with IL-1 family cytokine antagonists. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) has garnered considerable attention due to its morbidity and mortality. Although the precise mechanisms underlying HCC tumorigenesis remain to be elucidated, evidence suggests that host immunity plays a pivotal role in its development. IL-36 and IL-37 are important immunoregulatory cytokines classified as pro-inflammatory and anti-inflammatory respectively. In the context of HCC, the downregulation of intrahepatic IL-36 is inversely correlated with cirrhosis, but positively correlated with 5-year survival rates, suggesting that IL-36 offers protection during HCC development. However, IL-36 may lose its hepatoprotective effects as the disease progresses to HCC in the context of dysregulated immunity in cirrhotic patients. Substantially increased circulating IL-36 in HCC patients is likely a systemic response to HCC stimulation, but is insufficient to suppress progression towards HCC. Intrahepatic IL-37 is suppressed in HCC patients, consistent with the inverse correlation between intrahepatic IL-37 and the level of AFP in HCC patients, suggesting IL-37 exerts hepatoprotection. There is no significant difference in IL-37 among differentiations of HCC or with respect to clinical BCLC stages or cirrhosis status in HCC patients. However, IL-37 protection is demonstrated in an IL-37 transfected HCC animal model, showing significantly reduced tumour size. IL-36/37 may inhibit HCC by enhancing M1 tumour-associated macrophages while not affecting M2 macrophages. The interplay between IL-36 (pro-inflammatory) and IL-37 (anti-inflammatory) is emerging as a crucial factor in host protection against the development of HCC. Further research is needed to investigate the complex mechanisms involved and the therapeutic potential of targeting these cytokines in HCC management. [ABSTRACT FROM AUTHOR]

Interleukin (IL)-36 family is closely associated with inflammation and consists of IL-36α, IL-36β, IL-36γ, and IL-36Ra. The role of IL-36 in the context of asthma and asthmatic phenotypes is not well characterized. We examined the sputum IL-36 levels in patients with different asthma phenotypes in order to unravel the mechanism of IL-36 in different asthma phenotypes. Our objective was to investigate the induced sputum IL-36α, IL-36β, IL-36γ, and IL-36Ra concentrations in patients with mild asthma, and to analyze the relationship of these markers with lung function and other cytokines in patients with different asthma phenotypes. Induced sputum samples were collected from patients with mild controlled asthma (n = 62, 27 males, age 54.77 ± 15.49) and healthy non-asthmatic controls (n = 16, 10 males, age 54.25 ± 14.60). Inflammatory cell counts in sputum were determined. The concentrations of IL-36 and other cytokines in the sputum supernatant were measured by ELISA and Cytometric Bead Array. This is the first study to report the differential expression of different isoforms of IL-36 in different asthma phenotypes. IL-36α and IL-36β concentrations were significantly higher in the asthma group (P = 0.003 and 0.031), while IL-36Ra concentrations were significantly lower (P < 0.001) compared to healthy non-asthmatic controls. Sputum IL-36α and IL-36β concentrations in the neutrophilic asthma group were significantly higher than those in paucigranulocytic asthma (n = 24) and eosinophilic asthma groups (n = 23). IL-36α and IL-36β showed positive correlation with sputum neutrophils and total cell count (R = 0.689, P < 0.01; R = 0.304, P = 0.008; R = 0.689, P < 0.042; R = 0.253, P = 0.026). In conclusion, IL-36α and IL-36β may contribute to asthma airway inflammation by promoting neutrophil recruitment in airways. Our study provides insights into the inflammatory pathways of neutrophilic asthma and identifies potential therapeutic target. [ABSTRACT FROM AUTHOR]

Pyodermatitis pyostomatitis vegetans is a rare inflammatory condition, affecting the skin and/or mucous membrane. Some cases include both skin and mucous involvement, whereas others develop either skin or mucous lesions only. The typically affected areas are the scalp, face, trunk and extremities, including the flexural areas and umbilicus. Clinical features show erosive granulomatous plaques, keratotic plaques with overlying crusts and pustular lesions. Among mucous lesions, oral mucosa is most frequently involved, and gingival erythema, shallow erosions, cobblestone‐like papules on the buccal mucosa or upper hard palate of the oral cavity are also observed. Some of the lesions assume a 'snail track' appearance. Although there are several similarities between pyodermatitis pyostomatitis vegetans and other diseases, that is pyoderma gangrenosum, pemphigus vegetans and pemphigoid vegetans, the histopathological features of pyodermatitis pyostomatitis vegetans are unique in that epidermal hyperplasia, focal acantholysis and dense inflammatory infiltrates with intraepidermal and subepidermal eosinophilic microabscesses are observed. Direct immunofluorescence findings are principally negative. Activated neutrophils are supposed to play an important role in the pathogenesis of pyodermatitis pyostomatitis vegetans. The expression of IL‐36 and neutrophil extracellular traps (NETs) was observed in the lesional skin, and additionally, eosinophil extracellular traps (EETs) was detected in pyodermatitis pyostomatitis vegetans. A possible pathogenic role of NETs and EETs in the innate immunity and autoinflammatory aspects of pyodermatitis pyostomatitis vegetans was discussed. [ABSTRACT FROM AUTHOR]

Jason E Hawkes,1,&ast; Dale V Reisner,2 Tina Bhutani3,&ast; 1Department of Dermatology, University of California at Davis, Sacramento, CA, USA; 2Patient Author, Yankton, SD, USA; 3Psoriasis and Skin Treatment Center, Department of Dermatology, University of California at San Francisco, San Francisco, CA, USA&ast;These authors contributed equally to this workCorrespondence: Tina Bhutani, Email tina.bhutani@ucsf.eduAbstract: Generalized pustular psoriasis (GPP) is a rare, chronic, and debilitating disease characterized by flares of widespread erythema, desquamation, and pustule formation. GPP flares can be accompanied by systemic symptoms including fever, fatigue, malaise, and skin pain; severe cases may be fatal if untreated. Although GPP may occur concurrently with plaque psoriasis, they represent two distinct inflammatory conditions. Patients with GPP experience a substantial burden of disease, and the impact of GPP on an individual’s mental health and quality-of-life (QoL) goes far beyond skin pain and discomfort. The rarity of GPP may result in a misdiagnosis, as the sudden onset of skin pustules may be mistaken for a primary infection. Misdiagnosis with a subsequent delay in treatment has tremendous negative consequences for the affected patient. In September 2022, spesolimab became the first FDA-approved medication in the US for the treatment of GPP flares in adults. Spesolimab has since been approved by regulatory agencies in numerous countries, including Japan, Mainland China, and the EU. Prior to spesolimab, the clinical management of GPP relied on the off-label use of systemic or biologic therapies approved for plaque psoriasis or other inflammatory conditions. There is a need for increased education among healthcare providers regarding the clinical diagnosis, risk stratification, and therapeutic management of this rare disease, including the other novel GPP-specific therapies in development. In this podcast, two dermatologists and a patient who has plaque psoriasis and GPP discuss the clinical presentation, symptoms, disease burden, QoL impacts, diagnostic challenges, and therapeutic strategies for the management of GPP.Keywords: generalized pustular psoriasis, GPP, pustules, quality-of-life, IL-36, spesolimab, plaque psoriasis, inflammatory skin disease

Background: Sepsis is defined as a life-threatening syndrome caused by an unbalanced host response to infection. The role of interleukin (IL)-36 cytokines binding to the IL-36 receptor (IL-36R) in host response during sepsis remains unknown. Methods: Serum IL-36 level was measured in 47 septic patients sampled on the day of intensive care unit (ICU) and emergency department admission, 21 non-septic ICU patient controls, and 21 healthy volunteers. In addition, the effects of IL-36R deletion on host inflammatory response in cecal ligation and puncture (CLP)-induced polymicrobial sepsis was determined. Results: On the day of ICU and emergency department admission, the patients with sepsis showed a significant increase in serum IL-36 levels compared with ICU patient controls and healthy volunteers, and the serum IL-36 levels were related to the severity of sepsis. Non-survivors of septic patients displayed significantly lower serum IL-36 levels compared with survivors. A high serum IL-36 level in ICU and emergency department admission was associated with 28-day mortality, and IL-36 was found to be an independent predictor of 28-day mortality in septic patients by logistic regression analysis. Furthermore, IL-36R deletion increased lethality in CLP-induced polymicrobial sepsis. Septic mice with IL-36R deletion had higher bacterial load and demonstrated more severe multiple organ injury (including lung, liver, and kidney) as indicated by clinical chemistry and histopathology. Mechanistically, IL-36R ligands released upon lung damage activated IL-36R+lung fibroblasts thereby inducing expression of the antimicrobial protein lipocalin 2. Moreover, they induced the apoptosis of lung epithelial cells. Conclusions: Septic patients had elevated serum IL-36 levels, which may correlate with disease severity and mortality. In experimental sepsis, we demonstrated a previously unrecognized role of IL-36R deletion in increasing lethality. [ABSTRACT FROM AUTHOR]

Generalized pustular psoriasis (GPP) is a rare, chronic, inflammatory skin disorder characterized by recurrent flares associated with skin erythema, desquamation, and widespread superficial sterile pustules, which may be severe (“lakes of pus”). Systemic symptoms are often present, including malaise, fever, and skin pain. In GPP, innate immune responses are driven by abnormal activation of the interleukin (IL)-36-chemokine-neutrophil axis and excessive neutrophil infiltration. This review highlights the IL-36 pathway in the context of the IL-1 superfamily and describes how unopposed IL-36 signaling can lead to the development of GPP. Targeted inhibition of the IL-36 receptor (IL-36R) is an attractive therapeutic strategy in the treatment of GPP, including flare prevention and sustained disease control. Spesolimab is a first-in-class, humanized, monoclonal antibody that binds specifically to the IL-36R and antagonizes IL36 signaling. Spesolimab was approved by the US Food and Drug Administration in September 2022 to treat GPP flares in adults and was subsequently approved for GPP flare treatment in other countries across the world. Anti-IL-36R therapy, such as spesolimab, can mitigate flares and address flare prevention in GPP, presumably through rebalancing IL-36 signaling and modulating the proinflammatory response of the downstream effectors. [ABSTRACT FROM AUTHOR]

This review explores the intricate relationship between generalized pustular psoriasis (GPP) and various systemic diseases, shedding light on the broader impacts of this severe skin condition beyond its primary dermatological manifestations. GPP is identified as not only a profound contributor to skin pathology but also a significant risk factor for systemic diseases affecting cardiovascular, hepatic, renal, pulmonary, and skeletal systems, as well as associated with an increased incidence of anemia, depression, anxiety, and arthritis. The research highlights the complex interplay of cytokines, particularly IL-17 and IL-36, which are central to the pathophysiology of GPP and implicated in the exacerbation of systemic conditions. Key findings indicate a higher incidence of cardiovascular events in GPP patients compared to those with other severe forms of psoriasis, notably with a stronger correlation between myocardial infarction history and GPP development. Liver disturbances, frequently reversible upon psoriasis remission, suggest a cytokine-mediated link to hepatic health. Renal dysfunction appears elevated in GPP sufferers, with IL-17 and IL-36 potentially driving renal fibrosis. Similarly, interstitial lung disease and osteoporosis in GPP patients underscore the systemic reach of inflammatory processes initiated in the skin. The associations with anemia, depression, anxiety, and arthritis further complicate the clinical management of GPP, requiring a multidisciplinary approach. The study concludes that managing GPP effectively requires a holistic approach that addresses both the cutaneous and systemic dimensions of the disease, advocating for continued research into the mechanisms that connect GPP with broader health implications to refine therapeutic strategies.

IL-36 cytokines are emerging as beneficial in immunity against pathogens and cancers but can also be detrimental when dysregulated in autoimmune and autoinflammatory conditions. Interest in targeting IL-36 activity for therapeutic purposes is rapidly growing, yet many unknowns about the functions of these cytokines remain. Thus, the availability of robust research tools is essential for both fundamental basic science and pre-clinical studies to fully access outcomes of any manipulation of the system. For this purpose, a floxed Il1rl2, the gene encoding the IL-36 receptor, mouse strain was developed to facilitate the generation of conditional knockout mice. The targeted locus was engineered to contain an inverted mCherry reporter sequence that upon Cre-mediated recombination will be flipped and expressed under the control of the endogenous Il1rl2 promoter. This feature can be used to confirm knockout in individual cells but also as a reporter to determine which cells express the IL-36 receptor IL-1RL2. The locus was confirmed to function as intended and further used to demonstrate the expression of IL-1RL2 in barrier tissues. Il1rl2 expression was detected in leukocytes in all barrier tissues. Interestingly, strong expression was observed in epithelial cells at locations in direct contact with the environment such as the skin, oral mucosa, the esophagus, and the upper airways, but almost absent from epithelial cells at more inward facing sites, including lung alveoli, the small intestine, and the colon. These findings suggest specialized functions of IL-1RL2 in outward facing epithelial tissues and cells. The generated mouse model should prove valuable in defining such functions and may also facilitate basic and translational research.

Generalized pustular psoriasis (GPP) is a rare, chronic, inflammatory skin disorder characterized by recurrent flares associated with skin erythema, desquamation, and widespread superficial sterile pustules, which may be severe (“lakes of pus”). Systemic symptoms are often present, including malaise, fever, and skin pain. In GPP, innate immune responses are driven by abnormal activation of the interleukin (IL)-36-chemokine-neutrophil axis and excessive neutrophil infiltration. This review highlights the IL-36 pathway in the context of the IL-1 superfamily and describes how unopposed IL-36 signaling can lead to the development of GPP. Targeted inhibition of the IL-36 receptor (IL-36R) is an attractive therapeutic strategy in the treatment of GPP, including flare prevention and sustained disease control. Spesolimab is a first-in-class, humanized, monoclonal antibody that binds specifically to the IL-36R and antagonizes IL-36 signaling. Spesolimab was approved by the US Food and Drug Administration in September 2022 to treat GPP flares in adults and was subsequently approved for GPP flare treatment in other countries across the world. Anti-IL-36R therapy, such as spesolimab, can mitigate flares and address flare prevention in GPP, presumably through rebalancing IL-36 signaling and modulating the pro-inflammatory response of the downstream effectors.

Endometrial Cancer (EC) is one of the most common malignancy of the female reproductive system. With an increasing incidence, it is important to improve the new prognosis ways for its pre-diagnosis that must be early, accurate and effective. This study aimed to search for biological (like some new interleukins) which could help in early diagnosis of EC before the hysterectomy. Currently not enough research is being done exploiting linking between the interleukins submitted in this study and EC. Epically IL-36 and IL-38, which have been recently described and are still under study in the world. This study is the first of its kind in Iraq. Fifty-five patients with EC (mainly in their first or second stage, due to early diagnosis and who newly have the symptoms and pain as a result of cancer) and 57 healthy controls (with ages up to 45) were involved in this study. To measure the concentration of the following interleukins: IL-27, 31, 33, 35, 36 and 38 by ELISA, blood samples were collected from women via vein puncture. The results of this study showed a highly significant (P≤0.01) increase in Interleukin 27 (IL-27), Interleukin 31 (IL-31) and Interleukin 33 (IL-33) among all studied interleukins levels in EC patient as compared with healthy controls. Interleukin 35 (IL-35), Interleukin 36 (IL-36) and Interleukin 38 (IL-38) also showed highly significant (P≤0.01) increase in EC patients as compared with healthy women. The significant increase (P≤0.01) of these interleukins can be used to help in the early diagnosis and treatment of EC, without need to hysterectomy or histological diagnosis. [ABSTRACT FROM AUTHOR]

Psoriasis is a chronic, immune‐mediated skin disease that affects over 3% of adults in the United States. Psoriasis can present in several clinical forms. Of these, generalized pustular psoriasis is an acute, severe form, associated with increased morbidity and mortality. Unlike the more common plaque psoriasis, which is thought to feature dysregulation of the adaptive immune system, generalized pustular psoriasis reflects heightened autoinflammatory responses. Recent advances in genetic and immunological studies highlight a key role of the IL‐36 immune axis in the pathogenesis of generalized pustular psoriasis. In this article, we review the psoriatic subtypes and discuss diagnostic criteria of generalized pustular psoriasis, discuss several newly identified genetic variants associated with pustular disease in the skin, and discuss how these mutations shed light on pustular disease mechanisms. Furthermore, we gather insights from recent transcriptomic studies that similarly implicate a pathogenic role of the IL‐36 immune axis in generalized pustular psoriasis. [ABSTRACT FROM AUTHOR]

Generalized pustular psoriasis (GPP) is a rare subset of psoriasis involving episodes of sterile pustules accompanied by inflammation and, often, systemic involvement. The inflammatory nature of GPP has potential for severe multisystem complications including high‐output cardiac failure, infections, digestive system issues, and disfiguring or lethal acute flare episodes. The disease tends to have higher prevalence in females and Asians. The IL‐1/IL‐36 inflammatory pathway is a critical facet of GPP's pathology. Genetic mutations that are associated with GPP include modifications of Interleukin 36 Receptor Antagonist (IL36RN), Caspase Recruitment Domain Family Member 14 (CARD14), Adaptor Related Protein Complex 1 Subunit Sigma 3 (AP1S3), Myeloperoxidase (MPO) and Serpin Peptidase Inhibitor Clade A Member 3 (SERPINA3) genes. Treatment guidelines for GPP are not well‐entrenched. Currently, only one GPP‐specific treatment, the interleukin‐36 receptor antagonist (IL‐36Ra) spesolimab, has been approved for use in the United States. Additional anti‐IL‐36 pathway therapies are currently being developed. Other treatment options include other biologic therapies such as IL‐17 inhibitors, IL‐23 inhibitors and TNFα inhibitors. Non‐biologic therapeutic options include retinoids, cyclosporine and methotrexate. Treatment options differ throughout the world; most countries utilize retinoids, cyclosporine and methotrexate as first‐line non‐biologic options. China and United Kingdom have no GPP‐specific biologic therapies approved for use, while several biologic therapies are approved for use in Japan. This review aims to serve as an update on the current global management of GPP while also including relevant aspects of disease pathogenesis, diagnosis, clinical presentation, histopathology, aetiology and epidemiology. [ABSTRACT FROM AUTHOR]

Generalised pustular psoriasis (GPP) is a rare and severe neutrophilic skin disorder, manifesting with acute episodes of pustulation and systemic upset. The discovery of recessive IL36RN mutations associated with GPP has transformed our understanding of disease drivers, paving the way for the development of targeted anti‐IL36 therapeutics. In the light of these remarkable successes, this viewpoint reviews the significance of IL36RN mutations in GPP, their functional impact and their correlation with clinical phenotypes. It then covers the discovery of further genetic determinants (recessive MPO mutations) and risk factors (AP1S3 and CARD14 low‐frequency variants) for the disease. It discusses the growing evidence for genetic complexity in GPP and concludes by outlining collaborative strategies that may be adopted to overcome the challenges ahead. [ABSTRACT FROM AUTHOR]

Key Clinical Message: IL‐36 might play a role as an initial immune mechanism against chikungunya fever, and regulating IL‐36 production could be a potential treatment approach for this condition. Two Japanese siblings visited Cook Islands in 2015 and developed Chikungunya fever upon their return. The sister experienced high fever, joint pain, and leg swelling, while the brother had joint pain and a rash. Both siblings had a confirmed CHIKV infection and continued to experience prolonged joint pain, with the sister enduring chronic pain for about a year. In this study, the levels of IL‐36 in the serum of two siblings who were infected with chikungunya fever during the acute and recovery phases were compared using ELISA. IL‐36 is a cytokine that induces inflammation and is produced by cells in tissues such as the skin and mucosa. It was hypothesized that IL‐36 may be involved in persistent joint pain after chikungunya fever infection. Both siblings experienced long‐lasting joint pain after chikungunya fever infection. The levels of IL‐36α and IL‐36β decreased by 56 days after infection. In the results, IL‐36 plays an important role in host immunity and may act as part of the immune response during chikungunya virus infection. Inhibiting the release of IL‐36 could be a promising approach for developing new treatment methods for chikungunya fever. [ABSTRACT FROM AUTHOR]

Effisayil 1 was a randomized, placebo-controlled study of spesolimab, which is an anti-IL-36 receptor antibody, in patients presenting with a generalized pustular psoriasis flare. To assess the effects of spesolimab over the 12-week study. The primary endpoint of the study was Generalized Pustular Psoriasis Physician Global Assessment (GPPGA) pustulation subscore of 0 at week 1. Patients (N = 53) were randomized (2:1) to receive a single intravenous dose of 900 mg spesolimab or placebo on day 1. Patients could receive open-label spesolimab for persistent flare symptoms on day 8. Most patients receiving spesolimab achieved a GPPGA pustulation subscore of 0 (60.0%) and GPPGA total score of 0 or 1 (60.0%) by week 12. In patients randomized to placebo who received open-label spesolimab on day 8, the proportion with GPPGA pustulation subscore of 0 increased from 5.6% at day 8 to 83.3% at week 2. No factors predictive of spesolimab response were identified in patient demographics or clinical characteristics. The effect of initial randomization was not determined conventionally beyond week 1 due to patients receiving open-label spesolimab. Rapid control of generalized pustular psoriasis flare symptoms with spesolimab was sustained over 12 weeks, further supporting its potential use as a therapeutic option for patients. [ABSTRACT FROM AUTHOR]

Psoriasis is a chronic inflammatory skin condition that has a fairly wide range of clinical presentations. Plaque psoriasis, which is the most common manifestation of psoriasis, is located on one end of the spectrum, dominated by adaptive immune responses, whereas the rarer pustular psoriasis lies on the opposite end, dominated by innate and autoinflammatory immune responses. In recent years, genetic studies have identified six genetic variants that predispose to pustular psoriasis, and these have highlighted the role of IL-36 cytokines as central to pustular psoriasis pathogenesis. In this review, we discuss the presentation and clinical subtypes of pustular psoriasis, contribution of genetic predisposing variants, critical role of the IL-36 family of cytokines in disease pathophysiology, and treatment perspectives for pustular psoriasis. We further outline the application of appropriate mouse models for the study of pustular psoriasis and address the outstanding questions and issues related to our understanding of the mechanisms involved in pustular psoriasis.

Abstract Generalized pustular psoriasis (GPP) is a rare, chronic, and severe inflammatory skin disorder characterized by sudden eruption of sterile pustules, often accompanied by systemic inflammation. GPP flares can be life-threatening if untreated, owing to potential serious complications such as sepsis and cardiovascular failure. Diagnosis and clinical measurement of disease severity in GPP are often difficult. Lack of standardized criteria in the international guidelines and the heterogeneity of cutaneous and extracutaneous symptoms make the diagnosis of GPP difficult. Clinical criteria for description and diagnosis of pustular conditions, including GPP, are variable and there is no specific agreement on commonly sustained concepts. Differentiation of GPP from other similar conditions/diseases is important and requires careful assessments. The evidence that supports current topical or systemic therapies is largely based on case reports and small studies. Some biologic agents that target key cytokines involved in the activation of inflammatory pathways have been used as treatments for GPP. Recently, spesolimab, an IL-36R antagonist, has been approved in the USA and Japan for the treatment of GPP flares in adults, but there are no currently approved treatments for GPP in Europe. The IL-36 pathway has recently emerged as a central axis driving the pathogenic inflammatory mechanisms of GPP. Biologic agents that inhibit the IL-36 pathway have shown efficacy and safety in patients with GPP, addressing a generally considered unmet medical need.

The immunopathogenesis of HS is partially understood and exhibits features of an autoinflammatory disease; it is associated with the potential involvement of B cells and the contribution of Th1 or Th17 cell subsets. Recently, the pathogenic role of both innate immunity and IL-1 family cytokines in HS has been deeply investigated. Several agents targeting the IL-1 family pathway at different levels are currently available and under investigation for the treatment of HS. HS is still characterized by unmet clinical needs and represents an expanding field in the current scientific research. The aim of this narrative review is to describe the pathological dysregulation of IL-1 family members in HS and to provide an update on therapeutic strategies targeting IL-1 family cytokine signaling. Further clinical and preclinical data may likely lead to the enrichment of the therapeutic armamentarium of HS with IL-1 family cytokine antagonists.

Key Clinical Message IL‐36 might play a role as an initial immune mechanism against chikungunya fever, and regulating IL‐36 production could be a potential treatment approach for this condition. Abstract Two Japanese siblings visited Cook Islands in 2015 and developed Chikungunya fever upon their return. The sister experienced high fever, joint pain, and leg swelling, while the brother had joint pain and a rash. Both siblings had a confirmed CHIKV infection and continued to experience prolonged joint pain, with the sister enduring chronic pain for about a year. In this study, the levels of IL‐36 in the serum of two siblings who were infected with chikungunya fever during the acute and recovery phases were compared using ELISA. IL‐36 is a cytokine that induces inflammation and is produced by cells in tissues such as the skin and mucosa. It was hypothesized that IL‐36 may be involved in persistent joint pain after chikungunya fever infection. Both siblings experienced long‐lasting joint pain after chikungunya fever infection. The levels of IL‐36α and IL‐36β decreased by 56 days after infection. In the results, IL‐36 plays an important role in host immunity and may act as part of the immune response during chikungunya virus infection. Inhibiting the release of IL‐36 could be a promising approach for developing new treatment methods for chikungunya fever.

Background IL-36 cytokines are members of the IL-1 superfamily. Increasing evidence in the IL-36 pathway demonstrates their potential as a therapeutic target for treating inflammatory skin diseases, such as generalized pustular psoriasis (GPP). Objective A narrative review was written to further study preclinical and clinical evidence for the role of IL-36 in psoriasis, atopic dermatitis (AD), hidradenitis suppurativa (HS), acne, autoimmune blistering diseases, and neutrophilic dermatoses. Results IL-36 has important downstream effects such as inducing expression of inflammatory cytokines, antimicrobial peptides, and growth factors. Increased expression of IL-36 cytokines has been observed in the lesional skin of patients with psoriasis. Studies of other inflammatory skin diseases have also noted similar findings, albeit to a lesser extent. IL-36 inhibition has been shown to be effective in GPP and is currently being studied for other inflammatory skin diseases. Conclusions The IL-36 pathway contributes to pathogenesis of many inflammatory skin diseases and is a promising therapeutic target.

Purpose: Epithelial–mesenchymal transition (EMT) is an important characteristic in the remodelling of chronic rhinosinusitis with nasal polyps (CRSwNP). IL‐36γ and fibroblast activation protein (FAP) may exacerbate remodelling in CRS. Here, we aimed to determine whether IL‐36γ and FAP expression are associated with EMT and may be a predictor for CRSwNP prognosis. Methods: Fifty‐two non‐Eos CRSwNP patients and 12 control patients were obtained and were followed up for more than 1 year after surgery. IL‐36γ, FAP and EMT markers expression were evaluated by real‐time polymerase chain reaction and western blot. Masson trichrome staining was adopted to assess tissue fibrotic changes. Furthermore, the soluble form of IL‐36γ and FAP in nasal secretions was detected by ELISA. Results: While basal expression of E‐cadherin decreased, the expression of IL‐36γ, vimentin and FAP increased in nasal polyps. In well‐prognosis patients, the expression of IL‐36γ, vimentin and FAP were significantly decreased than in poor‐prognosis patients, while the protein expression of E‐cadherin was increased. The protein expression of IL‐36γ was notably increased in recurrent nasal polyps than in preoperation specimens. A positive relationship between IL‐36γ and FAP expression, a negative relationship between IL‐36γ and E‐cad expression was noted. The soluble form of IL‐36γ and FAP increased during the development of non‐Eos CRSwNP, with the highest level in poor‐prognosis patients after surgery. Conclusion: Non‐Eos CRSwNP have partially undergone EMT under baseline conditions. IL‐36γ and FAP expression were related with EMT, the soluble form of IL‐36γ and FAP in nasal secretions may predict the prognosis of patients. [ABSTRACT FROM AUTHOR]

Generalized pustular psoriasis (GPP) is a rare, chronic, and severe inflammatory skin disorder characterized by sudden eruption of sterile pustules, often accompanied by systemic inflammation. GPP flares can be life-threatening if untreated, owing to potential serious complications such as sepsis and cardiovascular failure. Diagnosis and clinical measurement of disease severity in GPP are often difficult. Lack of standardized criteria in the international guidelines and the heterogeneity of cutaneous and extracutaneous symptoms make the diagnosis of GPP difficult. Clinical criteria for description and diagnosis of pustular conditions, including GPP, are variable and there is no specific agreement on commonly sustained concepts. Differentiation of GPP from other similar conditions/diseases is important and requires careful assessments. The evidence that supports current topical or systemic therapies is largely based on case reports and small studies. Some biologic agents that target key cytokines involved in the activation of inflammatory pathways have been used as treatments for GPP. Recently, spesolimab, an IL-36R antagonist, has been approved in the USA and Japan for the treatment of GPP flares in adults, but there are no currently approved treatments for GPP in Europe. The IL-36 pathway has recently emerged as a central axis driving the pathogenic inflammatory mechanisms of GPP. Biologic agents that inhibit the IL-36 pathway have shown efficacy and safety in patients with GPP, addressing a generally considered unmet medical need. [ABSTRACT FROM AUTHOR]

Preterm birth is a major contributor to neonatal morbidity and mortality. Complications of prematurity such as bronchopulmonary dysplasia (BPD, affecting the lung), pulmonary hypertension associated with BPD (BPD-PH, heart), white matter injury (WMI, brain), retinopathy of prematurity (ROP, eyes), necrotizing enterocolitis (NEC, gut) and sepsis are among the major causes of long-term morbidity in infants born prematurely. Though the origins are multifactorial, inflammation and in particular the imbalance of pro- and anti-inflammatory mediators is now recognized as a key driver of the pathophysiology underlying these illnesses. Here, we review the involvement of the interleukin (IL)-1 family in perinatal inflammation and its clinical implications, with a focus on the potential of these cytokines as therapeutic targets for the development of safe and effective treatments for early life inflammatory diseases. [ABSTRACT FROM AUTHOR]

Trained immunity is the process of long-term functional reprogramming (a de facto innate immune memory) of innate immune cells such as monocytes and macrophages after an exposure to pathogens, vaccines, or their ligands. The induction of trained immunity is mediated through epigenetic and metabolic mechanisms. Apart from exogenous stimuli, trained immunity can be induced by endogenous compounds such as oxidized LDL, urate, fumarate, but also cytokines including IL-1α and IL-1β. Here, we show that also recombinant IL-36γ, a pro-inflammatory cytokine of the IL-1-family, is able to induce trained immunity in primary human monocytes, demonstrated by higher cytokine responses and an increase in cellular metabolic pathways both regulated by epigenetic histone modifications. These effects could be inhibited by the IL-36 receptor antagonist as well as by IL-38, an anti-inflammatory cytokine of the IL-1 family which shares its main receptor with IL-36 (IL-1R6). Further, we demonstrated that trained immunity induced by IL-36γ is mediated by NF-κB and mTOR signaling. The inhibitory effect of IL-38 on IL-36γ-induced trained immunity was confirmed in experiments using bone marrow of IL-38KO and WT mice. These results indicate that exposure to IL-36γ results in long-term pro-inflammatory changes in monocytes which can be inhibited by IL-38. Recombinant IL-38 could therefore potentially be used as a therapeutic intervention for diseases characterized by exacerbated trained immunity. [ABSTRACT FROM AUTHOR]

BackgroundFibrostenotic disease is a common complication in Crohn’s disease (CD) patients hallmarked by transmural extracellular matrix (ECM) accumulation in the intestinal wall. The prevention and medical therapy of fibrostenotic CD is an unmet high clinical need. Although targeting IL36R signaling is a promising therapy option, downstream mediators of IL36 during inflammation and fibrosis have been incompletely understood. Candidate molecules include matrix metalloproteinases which mediate ECM turnover and are thereby potential targets for anti-fibrotic treatment. Here, we have focused on understanding the role of MMP13 during intestinal fibrosis.MethodsWe performed bulk RNA sequencing of paired colon biopsies taken from non-stenotic and stenotic areas of patients with CD. Corresponding tissue samples from healthy controls and CD patients with stenosis were used for immunofluorescent (IF) staining. MMP13 gene expression was analyzed in cDNA of intestinal biopsies from healthy controls and in subpopulations of patients with CD in the IBDome cohort. In addition, gene regulation on RNA and protein level was studied in colon tissue and primary intestinal fibroblasts from mice upon IL36R activation or blockade. Finally, in vivo studies were performed with MMP13 deficient mice and littermate controls in an experimental model of intestinal fibrosis. Ex vivo tissue analysis included Masson’s Trichrome and Sirius Red staining as well as evaluation of immune cells, fibroblasts and collagen VI by IF analysis.ResultsBulk RNA sequencing revealed high upregulation of MMP13 in colon biopsies from stenotic areas, as compared to non-stenotic regions of patients with CD. IF analysis confirmed higher levels of MMP13 in stenotic tissue sections of CD patients and demonstrated αSMA+ and Pdpn+ fibroblasts as a major source. Mechanistic experiments demonstrated that MMP13 expression was regulated by IL36R signaling. Finally, MMP13 deficient mice, as compared to littermate controls, developed less fibrosis in the chronic DSS model and showed reduced numbers of αSMA+ fibroblasts. These findings are consistent with a model suggesting a molecular axis involving IL36R activation in gut resident fibroblasts and MMP13 expression during the pathogenesis of intestinal fibrosis.ConclusionTargeting IL36R-inducible MMP13 could evolve as a promising approach to interfere with the development and progression of intestinal fibrosis.

Siyuan Huang,1,&ast; Tao Feng,2,&ast; Jing Wang,1 Liang Dong3 1Department of Respiratory, Shandong Qianfoshan Hospital, Cheeloo College of Medicine, Shandong University, Jinan, People’s Republic of China; 2Department of Respiratory Medicine, Shengli Oilfield Central Hospital, Dongying, People’s Republic of China; 3Department of Respiratory, Shandong Provincial Qianfoshan Hospital, Shandong University, The First Affiliated Hospital of Shandong First Medical University, Shandong Institute of Respiratory Diseases, Jinan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Liang Dong, Department of Respiratory, Shandong Provincial Qianfoshan Hospital, Shandong University, The First Affiliated Hospital of Shandong First Medical University, Shandong Institute of Respiratory Diseases, Jinan, 250014, People’s Republic of China, Tel +86-13505401207, Email dl5506@126.comBackground: Interleukin (IL)-36α, IL-36β, and IL-36γ belong to the IL-36 family and play an important role in the pathogenesis of many diseases. Chronic obstructive pulmonary disease (COPD) may be correlated with IL-36; however, the specific role of IL-36 in COPD is unclear. In this study, we aimed to clarify whether IL-36 could be an indicator for determining COPD severity and the specific nature of the pro-inflammatory effects of IL-36 in COPD.Methods: A total of 70 patients with COPD and 20 control subjects were included in this study. We collected peripheral blood samples from both the groups, analyzed the blood cell fractions by routine blood examination, and measured the serum levels of IL-36α, IL-36β, and IL-36γ by performing polymerase chain reaction and enzyme-linked immunosorbent assay. In addition, the correlation between the number of neutrophils and eosinophils and the level of IL-36 was also analyzed.Results: We found that level of IL-36 in patients with COPD was positively correlated with the number of neutrophils but not with eosinophils, whereas the correlation was not found in the control group. Moreover, the level of IL-36 was negatively correlated with the level of lung function of patients with COPD, and the levels of IL-36α, IL-36β, and IL-36γ increased with advancing disease severity.Conclusion: In COPD, the pro-inflammatory effect of IL-36 is closely related to neutrophils, and hence, IL-36 might be considered a novel biomarker for determining COPD severity.Keywords: chronic obstructive pulmonary disease, IL-36, neutrophils, inflammation

Background Growing evidence suggests the important role of IL-36 in the pathogenesis of psoriasis. Cathepsin G is a neutrophil-derived protease that can activate IL-36γ. Objective To assess the expression of IL-36γ and cathepsin G in psoriasis and to quantify the impact of treatment with narrow-band ultraviolet B phototherapy (NB-UVB) on their levels. Methods This case-control study involved 26 patients with moderate-severe psoriasis and 25 healthy volunteers. Psoriasis patients eligible for phototherapy received 24 NB-UVB sessions. Punch skin biopsies were obtained from all participants at recruitment and after phototherapy from patients. Real-time PCR was utilized for quantitative assessment of IL-36γ and cathepsin G expression in tissue samples. Results The expression of IL-36γ and cathepsin G was significantly higher in psoriasis before NB-UVB therapy compared to controls (p

Nikolaos Pournaras,1,2 Anders Andersson,3,4 Melissa A Kovach,1 Médea Padra,5 Karlhans F Che,1,2 Bettina Brundin,1 Shigemi Yoshihara,6 Steven Bozinovski,7 Sara K Lindén,5 Per-Anders Jansson,8 Magnus C Sköld,2,9 Ingemar Qvarfordt,3,8 Anders Lindén1,2 1Division for Lung and Airway Research, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; 2Karolinska Severe COPD Center, Department of Respiratory Medicine and Allergy, Karolinska University Hospital, Stockholm, Sweden; 3COPD Center, Department of Respiratory Medicine and Allergology, Sahlgrenska University Hospital, Gothenburg, Sweden; 4COPD Center, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; 5Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; 6Pediatric Allergology and Respiratory Medicine, Department of Pediatrics, Dokkyo Medical University, Mibu, Tochigi, Japan; 7School of Health and Biomedical Sciences, RMIT University, Bundoora, Victoria, Australia; 8Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; 9Division for Respiratory Medicine, Department of Medicine Solna, Karolinska Institutet, Stockholm, SwedenCorrespondence: Nikolaos Pournaras, Division for Lung and Airway Research, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden and Karolinska Severe COPD Center, Department of Respiratory Medicine and Allergy, Karolinska University Hospital, Stockholm, Sweden, Email nikolaos.pournaras@ki.sePurpose: Type 2 diabetes mellitus (T2DM) and metabolic syndrome (MetS) are common comorbidities in chronic obstructive pulmonary disease (COPD), but the underlying pathogenic mechanisms are poorly understood. Given that these morbidities all display increased neutrophil mobilization, the current study aimed to address whether glucose homeostasis relates to signs of neutrophil mobilization in COPD.Methods: The study population included healthy non-smokers (HNS) and long-term smokers without (LTS) and with COPD (LTS+COPD). No subject had T2DM or MetS. Serum cotinine was quantified to evaluate current smoking. Capillary blood glucose was measured after overnight fasting and during an oral glucose tolerance test (OGTT). Neutrophils were quantified in blood and bronchoalveolar lavage samples (BAL). The neutrophil-related cytokines IL-36α, -β and -γ were quantified (ELISA) along with IL-6, IL-8, INF-γ and CXCL10 (U-Plex®) in plasma and cell-free BAL fluid (BALF). In addition, we quantified neutrophil elastase (ELISA) and net proteinase activity (substrate assay) in BALF.Results: The LTS+COPD group had lower fasting glucose, greater change in glucose during OGTT and higher neutrophil concentrations in BAL and blood compared with HNS. Fasting glucose correlated in a positive manner with blood neutrophil concentration, forced expiratory volume in 1 second/forced vital capacity ratio (FEV1/FVC) and FEV1 (% of predicted) in LTS+COPD. In this group, the concentration of IL-36α in BALF correlated in a negative manner with fasting glucose, blood neutrophil concentration and FEV1, while the CXCL10 concentration in BALF correlated in a negative manner with glucose at the end of OGTT (120 min). We observed no corresponding correlations for neutrophil elastase, net proteinase or gelatinase activity.Conclusion: In smokers with COPD, altered glucose homeostasis is associated with local and systemic signs of increased neutrophil mobilization, but not with local proteinases. This suggests that other specific aspects of neutrophil mobilization constitute pathogenic factors that affect glucose homeostasis in COPD.Keywords: granulocyte, elastase, IL-36, IP-10, BAL

The IL-1 family of cytokines consists of IL-1α, IL-1β, IL-18, IL-33, IL-36α, IL-36β, and IL-36γ. These proteins form four signaling receptor complexes: the IL-1 receptor (IL-1R1 and IL-1RAcP), the IL-18 receptor (IL-18Rα and IL-18Rβ), the IL-33 receptor (ST2 and IL-1RAcP), and the IL-36 receptor (IL-1Rrp2 and IL-1RAcP). The formation of receptor complexes is also regulated by various antagonistic molecules and decoy receptors. The IL-1 family cytokines are induced and secreted by both innate immune cells and tissue cells upon infection and tissue damage. Thus, they play a diverse role in mediating both innate and adaptive immune responses. During tumor development and cancer treatment, the expression of the IL-1 gene family is differentially regulated in tumor cells, tissue stromal cells, and immune cells in a stage specific and tissue specific manner. Like other cytokines, the IL-1 family proteins have pleiotropic functions that are dependent on diverse arrays of target cells. As a result, they play a complex role in tumorigenesis, cancer metastasis, immune suppression, and cancer immune surveillance. Here, we focus on reviewing experimental evidence demonstrating how members of the IL-1 family influence cancer development at the cellular and molecular level. The unique mechanisms of this group of cytokines make them attractive targets for new cancer therapy. [ABSTRACT FROM AUTHOR]

• 2354Glu regulates ameliorated psoriasis by disturbing IL-36γ induced inflammatory loop via P2X7R. • dsRNA and ATP are responsible for the NET formation in psoriasis. • NET can be summoned by 2354Glu in psoriasis. Psoriasis, a chronic immune-mediated skin disease with pathological features such as aberrant differentiation of keratinocytes, dermal-epidermal inflammation, and angiogenesis. 2,3,5,4′-Tetrahydroxy stilbene 2-Ο-β- d -glucoside (2354Glu) is a natural small molecule polyhydrostilbenes isolated from Polygonum multiglorum Thunb. The regulation of IL-36 subfamily has led to new pharmacologic strategies to reverse psoriasiform dermatitis. Here we investigated the therapeutic potential of 2354Glu and elucidated the underlying mechanism in psoriasis. The effects of 2354Glu on IL-36 signaling were assessed by psoriasiform in vivo, in vitro and ex vivo model. The in vivo mice model of psoriasis-like skin inflammation was established by applying imiquimod (IMQ), and the in vitro and ex vitro models were established by stimulating mouse primary keratinocyte, human keratinocytes cells (HaCaT) and ex vivo skin tissue isolated from the mice back with Polyinosine-polycytidylic acid (Poly(I:C)), IMQ, IL-36γ and Lipopolysaccharide (LPS) respectively. Moreover, NETs formation was inhibited by Cl-amidine to evaluate the effect of NETs in psoriatic mouse model. The effects of 2354Glu on skin inflammation were assessed by western blot, H&E, immunohistochemistry, immunofluorescence, enzyme-linked immunosorbent assay and real-time quantitative PCR. In Poly(I:C)-stimulated keratinocytes, the secretion of IL-36 was inhibited after treatment with 2354Glu, similar to the effects of TLR3, P2X7R and caspase-1 inhibitors. In aldara (imiquimod)-induced mice, 2354Glu (100 and 25 mg/kg) improved immune cell infiltration and hyperkeratosis in psoriasis by directly targeting IL-36 in keratinocytes through P2X7R-caspase-1. When treatment with 2354Glu (25 mg/kg) was insufficient to inhibit IL-36γ, NETs reduced pathological features and IL-36 signaling by interacting with keratinocytes to combat psoriasis like inflammation. Conclusion: These results indicated that NETs had a beneficial effect on psoriasiform dermatitis. 2354Glu alleviates psoriasis by directly targeting IL-36/P2X7R axis and NET formation, providing a potential candidate for the treatment of psoriasis. [Display omitted] [ABSTRACT FROM AUTHOR]

Background. This article discusses issues of diagnosis and management of pustular psoriasis in a child associated with recurrent dermatomycosis, immunopathogenetic mechanisms of pustular psoriasis, its course and prognosis. Clinical Case Description. The clinical case of infiltrative-suppurative form of scalp microsporia in 11 years old child with long-term psoriasis vulgaris and its transformation to generalized pustular psoriasis (von Zumbusch) is described. The need of immunosuppressive therapy prescription for severe psoriasis was challenged with fungal skin infection as immune suppression would lead to its recurrent course. Conclusion. Combination treatment (systemic glucocorticosteroids, methotrexate, antibiotics, and griseofulvin) resulted in clinical and laboratory recovery for microsporia in a child with generalized pustular psoriasis.

IL-36 cytokines are members of the IL-1 superfamily. Increasing evidence in the IL-36 pathway demonstrates their potential as a therapeutic target for treating inflammatory skin diseases, such as generalized pustular psoriasis (GPP). A narrative review was written to further study preclinical and clinical evidence for the role of IL-36 in psoriasis, atopic dermatitis (AD), hidradenitis suppurativa (HS), acne, autoimmune blistering diseases, and neutrophilic dermatoses. IL-36 has important downstream effects such as inducing expression of inflammatory cytokines, antimicrobial peptides, and growth factors. Increased expression of IL-36 cytokines has been observed in the lesional skin of patients with psoriasis. Studies of other inflammatory skin diseases have also noted similar findings, albeit to a lesser extent. IL-36 inhibition has been shown to be effective in GPP and is currently being studied for other inflammatory skin diseases. The IL-36 pathway contributes to pathogenesis of many inflammatory skin diseases and is a promising therapeutic target. [ABSTRACT FROM AUTHOR]

The interleukin-1 (IL-1) family is involved in the correct functioning and regulation of the innate immune system, linking innate and adaptative immune responses. This complex family is composed by several cytokines, receptors, and co-receptors, all working in a balanced way to maintain homeostasis. Dysregulation of these processes results in tissue inflammation and is involved in the pathogenesis of common inflammatory dermatoses such as psoriasis, hidradenitis suppurativa, and atopic dermatitis. Therefore, therapeutic targeting of IL-1 pathways has been studied, and several monoclonal antibodies are currently being assessed in clinical trials. So far, promising results have been obtained with anti-IL-36R spesolimab and imsidolimab in pustular psoriasis, and their efficacy is being tested in other conditions. [ABSTRACT FROM AUTHOR]

Interleukin (IL)-36 cytokines are members of the IL-1 superfamily, which consists of three agonists (IL-36a, IL-36b and IL-36g) and an IL-36 receptor antagonist (IL-36Ra). IL-36 cytokines are crucial for immune and inflammatory responses. Abnormal levels of IL-36 cytokine expression are involved in the pathogenesis of inflammation, autoimmunity, allergy and cancer. The present study provides a summary of recent reports on IL-36 cytokines that participate in the pathogenesis of inflammatory diseases, and the potential mechanisms underlying their roles in asthma. Abnormal levels of IL-36 cytokines are associated with the pathogenesis of different types of asthma through the regulation of the functions of different types of cells. Considering the important role of IL-36 cytokines in asthma, these may become a potential therapeutic target for asthma treatment. However, existing evidence is insufficient to fully elucidate the specific mechanism underlying the action of IL-36 cytokines during the pathological process of asthma. The possible mechanisms and functions of IL-36 cytokines in different types of asthma require further studies. [ABSTRACT FROM AUTHOR]

Background: Acne vulgaris (AV) is an extraordinarily common skin condition. The high prevalence of AV is linked to the exposure factors, as environmental pollutants and climatic factors, occupational, psychosocial, and lifestyle factors. The AhR plays a critical part in environmental toxic action. The AhR expression and imbalance in the IL‐36 & 38 expression may have a role in inflammation and AV pathogenesis. Aims: To detect possible links between environmental, inflammatory, and anti‐inflammatory factors in AV pathogenesis through measuring AhR, IL‐36, and IL‐38 mRNA gene expression levels. Patients and Methods: Total of 100 subjects (70 AV patients and 30 apparently healthy control subjects) were tested for AhR, IL‐36γ, and IL‐38 mRNA levels by quantitative real‐time PCR. Results: The median levels of AhR and IL‐36 mRNA gene expression were considerably greater, while that of IL‐38 was essentially lower in AV than healthy subjects (p < 0.001, 0.021 and 0.002, respectively). The AhR and IL‐36 mRNA gene expression levels increased, while IL‐38 decreased significantly with higher grades of severity (p < 0.001, 0.001, and <0.001, respectively). ROC curve showed that AhR mRNA gene expression level had the best AUC for diagnosis of AV, with better sensitivity and specificity than IL‐36 and IL‐38. Conclusions: Higher levels of AhR, IL‐36, and lower levels of IL‐38 gene expression were significantly associated with AV patients and higher grades of severity. AhR had better diagnostic ability than IL‐38 and IL‐36. [ABSTRACT FROM AUTHOR]