A key role for IL-13 signaling via the type 2 IL-4 receptor in experimental atopic dermatitis

2020 ◽  
Vol 5 (44) ◽  
pp. eaaw2938 ◽  
Author(s):  
Almog Bitton ◽  
Shmuel Avlas ◽  
Hadar Reichman ◽  
Michal Itan ◽  
Danielle Karo-Atar ◽  
...  
Keyword(s):  
Atopic Dermatitis ◽  
Allergic Diseases ◽  
Proof Of Concept ◽  
Potential Therapeutic Target ◽  
Tnf Α ◽  
Allergic Skin ◽  
Insight Into

IL-13 and IL-4 are potent mediators of type 2–associated inflammation such as those found in atopic dermatitis (AD). IL-4 shares overlapping biological functions with IL-13, a finding that is mainly explained by their ability to signal via the type 2 IL-4 receptor (R), which is composed of IL-4Rα in association with IL-13Rα1. Nonetheless, the role of the type 2 IL-4R in AD remains to be clearly defined. Induction of two distinct models of experimental AD in Il13ra1−/− mice, which lack the type 2 IL-4R, revealed that dermatitis, including ear and epidermal thickening, was dependent on type 2 IL-4R signaling. Expression of TNF-α was dependent on the type 2 IL-4R, whereas induction of IL-4, IgE, CCL24, and skin eosinophilia was dependent on the type 1 IL-4R. Neutralization of IL-4, IL-13, and TNF-α as well as studies in bone marrow–chimeric mice revealed that dermatitis, TNF-α, CXCL1, and CCL11 expression were exclusively mediated by IL-13 signaling via the type 2 IL-4R expressed by nonhematopoietic cells. Conversely, induction of IL-4, CCL24, and eosinophilia was dependent on IL-4 signaling via the type 1 IL-4R expressed by hematopoietic cells. Last, we pharmacologically targeted IL-13Rα1 and established a proof of concept for therapeutic targeting of this pathway in AD. Our data provide mechanistic insight into the differential roles of IL-4, IL-13, and their receptor components in allergic skin and highlight type 2 IL-4R as a potential therapeutic target in AD and other allergic diseases such as asthma and eosinophilic esophagitis.

scholarly journals cAMP metabolism controls caspase-11 inflammasome activation and pyroptosis in sepsis

2019 ◽  
Vol 5 (5) ◽  
pp. eaav5562 ◽  
Author(s):  
Ruochan Chen ◽  
Ling Zeng ◽  
Shan Zhu ◽  
Jiao Liu ◽  
Herbert J. Zeh ◽  
...  
Keyword(s):  
Metabolic Pathways ◽  
Inflammatory Responses ◽  
Poly I:C ◽  
Inflammasome Activation ◽  
Proof Of Concept ◽  
Potential Therapeutic Target ◽  
Camp Metabolism ◽  
Camp Hydrolysis ◽  
Insight Into

The ability of cytosolic lipopolysaccharide (LPS) to activate caspase-11–dependent nonclassical inflammasome is intricately controlled to avoid excessive inflammatory responses. However, very little is known about the regulatory role of various metabolic pathways in the control of caspase-11 activation. Here, we demonstrate that l-adrenaline can act on receptor ADRA2B to inhibit the activation of the caspase-11 inflammasome by cytosolic LPS or Escherichia coli infection in macrophages. l-adrenaline–induced cAMP production via the enzyme ADCY4 promotes protein kinase A (PKA) activation, which then blocks the caspase-11–mediated proteolytic maturation of interleukin-1β, gasdermin D (GSDMD) cleavage, and consequent DAMP release. Inhibition of PDE8A-mediated cAMP hydrolysis limits caspase-11 inflammasome activation and pyroptosis in macrophages. Consequently, pharmacological modulation of the ADRA2B-ADCY4-PDE8A-PKA axis, knockout of caspase-11 (Casp11−/−), or Gsdmd inactivation (GsdmdI105N/I105N) similarly protects against LPS-induced lethality in poly(I:C)-primed mice. Our results provide previously unidentified mechanistic insight into immune regulation by cAMP and represent a proof of concept that immunometabolism constitutes a potential therapeutic target in sepsis.

scholarly journals miR-539 activates the SAPK/JNK signaling pathway to promote ferropotosis in colorectal cancer by directly targeting TIPE

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Yan Yang ◽  
Zeyang Lin ◽  
Zhaopu Han ◽  
Zhengxin Wu ◽  
Jianyu Hua ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
High Recurrence Rate ◽  
The Novel ◽  
Potential Therapeutic Target ◽  
Tnf Α ◽  
Jnk Signaling Pathway ◽  
The Relationship ◽  
Insight Into ◽  
Necrosis Factor

AbstractColorectal cancer (CRC) is a common tumor that harms human health with a high recurrence rate. It has been reported that the expression of microRNA-539 (miR-539) is low in several types of cancer, including CRC. Tumor necrosis factor (TNF)-α-induced protein 8 (TNFAIP8/TIPE) is highly expressed in CRC and promotes the proliferation, migration and angiogenesis of CRC. However, the relationship between miR-539 and TIPE and the mechanisms by which they regulate the proliferation of CRC remain to be explored. We aimed to investigate the functions and mechanisms of miR-539 in CRC proliferation. Functionally, miR-539 can bind to and regulate the expression of TIPE, and miR-539 activates SAPK/JNK to downregulate the expression of glutathione peroxidase 4 (GPX4) and promote ferroptosis. Our data reveal the novel role of miR-539 in regulating ferroptosis in CRC via activation of the SAPK/JNK axis, providing new insight into the mechanism of abnormal proliferation in CRC and a novel potential therapeutic target for advanced CRC.

scholarly journals The Role of Galectin-9 as Mediator of Atopic Dermatitis: Effect on Keratinocytes

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 947
Author(s):  
Mab P. Corrêa ◽  
Libnah L. Areias ◽  
Rebeca D. Correia-Silva ◽  
Solange C. G. P. D’Ávila ◽  
Andréia M. Leopoldino ◽  
...  
Keyword(s):  
Atopic Dermatitis ◽  
Human Keratinocytes ◽  
Allergic Diseases ◽  
Control Group ◽  
Biological Functions ◽  
Experimental Conditions ◽  
Control Growth ◽  
Tnf Α ◽  
Ifn Γ

Galectin-9 (Gal-9) is a beta-galactoside-binding protein with a variety of biological functions related to immune response. However, in allergic diseases, its mechanism of action is not fully understood. This study evaluates the expression pattern of Gal-9 in patients with atopic dermatitis (AD), in ovalbumin (OVA)-induced experimental atopic dermatitis (AD) in mice, as well as its effect on human keratinocytes. The skin of OVA-immunized BALB/c mice was challenged with drops containing OVA on days 11, 14–18, and 21–24. HaCaT cells were cultured in the following experimental conditions: control (growth medium only) or stimulated with TNF-α/IFN-γ, or IL-4, or IL-17 with or without Gal-9 treatment. AD was characterized by increased levels of Gal-9 in mouse and human skin, especially in the epidermis, and with a marked influx of Gal-9 positive eosinophils and mast cells compared to the control group. Gal-9 showed an immunomodulatory effect on keratinocytes by decreasing the release of IL-6 by IL-4-stimulated keratinocytes or increasing the IL-6 and RANTES levels by IL-17- or TNF-α/IFN-γ-stimulated cells, respectively. Under IL-17, Gal-9 treatment also altered the proliferation rate of cells. Overall, increased levels of Gal-9 in AD skin contribute to the control of inflammatory response and the proliferative process of keratinocytes, suggesting this lectin as a relevant therapeutic target.

Role of type 1 and type 2 T helper cells in allergic diseases

1992 ◽  
Vol 4 (6) ◽  
pp. 788-793 ◽  
Author(s):  
Martien L. Kapsenberg ◽  
Henk M. Jansen ◽  
Jan D. Bos ◽  
Eddy A. Wierenga
Keyword(s):  
T Helper Cells ◽  
Allergic Diseases ◽  
T Helper ◽  
Helper Cells

scholarly journals Discovering the Role of Emotional and Rational Appeals and Hidden Heterogeneity of Consumers in Advertising Copies for Sustainable Marketing

2020 ◽  
Vol 12 (12) ◽  
pp. 5189 ◽  
Author(s):  
Cheong Kim ◽  
Hyeon Gyu Jeon ◽  
Kun Chang Lee
Keyword(s):  
Unobserved Heterogeneity ◽  
Practical Implication ◽  
Marketing Strategies ◽  
Consumer Group ◽  
Sustainable Marketing ◽  
Type 3 ◽  
Insight Into

Advertising copies have been considered as a fundamental strategy for firms to continue sustainable marketing strategies. In order to provide the advancement of previous research and practical implication to marketers in the field for sustainable marketing strategy, this research tried to reveal the role of emotional and rational appeals as well as hidden heterogeneity of consumers in the appeal–value–trust–satisfaction–WOM framework. By applying the PLS-SEM and PLS-POS approach to 230 valid questionnaire samples, we could discover the role of appeals in the framework as well as three types of unobserved heterogeneity among the respondents. Both emotional and rational appeals had significant influences on the value–satisfaction–trust–WOM context. In addition, for hidden consumer traits in advertising copies, we revealed three types of consumer groups: Type 1, the consumer group with a rational orientation (n = 68); Type 2, the group with an emotional orientation (n = 74) and Type 3, the group with a utilitarian orientation. This research provided contributions by offering some insight into ways to establish sustainable marketing strategies in advertisements and to address unobserved heterogeneity consumers in advertising copy appeals.

ROLE OF PROINFLAMMATORY CYTOKINES IN PATHOGENESIS OF ARTHROPATHIES IN PATIENTS WITH DIABETES MELLITUS

2020 ◽  
Vol 73 (11) ◽  
pp. 2476-2481
Author(s):  
Valeriya L. Orlenko ◽  
Maria H. Kravchuk
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 1 Diabetes ◽  
Proinflammatory Cytokines ◽  
Joint Damage ◽  
Tnf Α ◽  
Patients With Diabetes

The aim: Of our work was to study the level of proinflammatory cytokines in patients with diabetic arthropathy and to investigate their possible effect on the development of this complication. Materials and methods: 118 patients were examined, which were divided into groups by type of diabetes, the presence and severity of diabetic arthropathy. The content of IL-1, TNF-α, IL-6 and receptors to S IL-6-R in serum was determined by immunoassay. Results: In patients with diabetic arthropathy, levels of TNF-α (with type 1 diabetes 44.5%, type 2 diabetes 42.9%) and IL-6 (with type 1 diabetes 52.1%, with diabetes 2 types by 64.4%) significantly increased. There is a direct correlation between the severity of joint damage and the level of TNF-α and IL-6. For IL -1, receptors for S IL-6-R have not been detected. Conclusions: The chances of detecting arthropathy with type 1 diabetes with increasing TNF levels increase by 1.7 times, with an increase in IL-6 by 1.5 times. For type 2 diabetes, it is 1.8 and 1.3 times, respectively. Thus, TNF-α and IL-6 may be markers of the presence and progression of arthropathy in patients with diabetes mellitus

scholarly journals Role of Oral Antioxidant Supplementation in the Current Management of Diabetic Retinopathy

2021 ◽  
Vol 22 (8) ◽  
pp. 4020
Author(s):  
Enrique Antonio Alfonso-Muñoz ◽  
Raquel Burggraaf-Sánchez de las Matas ◽  
Jorge Mataix Boronat ◽  
Julio César Molina Martín ◽  
Carmen Desco
Keyword(s):  
Diabetic Retinopathy ◽  
Diabetic Macular Oedema ◽  
Complementary Therapy ◽  
Antioxidant Supplementation ◽  
Current Management ◽  
Adult Type ◽  
Aged People

Oxidative stress has been postulated as an underlying pathophysiologic mechanism of diabetic retinopathy (DR), the main cause of avoidable blindness in working-aged people. This review addressed the current daily clinical practice of DR and the role of antioxidants in this practice. A systematic review of the studies on antioxidant supplementation in DR patients was presented. Fifteen studies accomplished the inclusion criteria. The analysis of these studies concluded that antioxidant supplementation has a IIB level of recommendation in adult Type 1 and Type 2 diabetes mellitus subjects without retinopathy or mild-to-moderate nonproliferative DR without diabetic macular oedema as a complementary therapy together with standard medical care.

scholarly journals EXPRESS: Pulmonary Hypertension Associated With Neurofibromatosis Type 2

2021 ◽  
pp. 204589402110295
Author(s):  
Hirohisa Taniguchi ◽  
Tomoya Takashima ◽  
Ly Tu ◽  
Raphaël Thuillet ◽  
Asuka Furukawa ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Neurofibromatosis Type ◽  
Pulmonary Vascular Remodeling ◽  
Life Threatening ◽  
History Of ◽  
Pulmonary Arterial ◽  
First Time

Although precapillary pulmonary hypertension (PH) is a rare but severe complication of patients with neurofibromatosis type 1 (NF1), its association with NF2 remains unknown. Herein, we report a case of a 44-year-old woman who was initially diagnosed with idiopathic pulmonary arterial hypertension (IPAH) and treated with PAH-specific combination therapy. However, a careful assessment for a relevant family history of the disease and genetic testing reveal that this patient had a mutation in the NF2 gene. Using immunofluorescence and Western blotting, we demonstrated a decrease in endothelial NF2 protein in lungs from IPAH patients compared to control lungs, suggesting a potential role of NF2 in PAH development. To our knowledge, this is the first time that precapillary PH has been described in a patient with NF2. The altered endothelial NF2 expression pattern in PAH lungs should stimulate work to better understand how NF2 is contributing to the pulmonary vascular remodeling associated to these severe life-threatening conditions.

scholarly journals Role of Bradykinin Type 2 Receptors in Human Sweat Secretion: Translational Evidence Does Not Support a Functional Relationship

2021 ◽  
Vol 34 (3) ◽  
pp. 162-166
Author(s):  
Thad E. Wilson ◽  
Seetharam Narra ◽  
Kristen Metzler-Wilson ◽  
Artur Schneider ◽  
Kelsey A. Bullens ◽  
...  
Keyword(s):  
Healthy Subjects ◽  
Sweat Rate ◽  
Sweat Glands ◽  
Potential Therapeutic Target ◽  
Sweat Secretion ◽  
Hoe 140 ◽  
A Current

Bradykinin increases skin blood flow via a cGMP mechanism but its role in sweating in vivo is unclear. There is a current need to translate cell culture and nonhuman paw pad studies into in vivo human preparations to test for therapeutic viability for disorders affecting sweat glands. Protocol 1: physiological sweating was induced in 10 healthy subjects via perfusing warm (46–48°C) water through a tube-lined suit while bradykinin type 2 receptor (B2R) antagonist (HOE-140; 40 μM) and only the vehicle (lactated Ringer’s) were perfused intradermally via microdialysis. Heat stress increased sweat rate (HOE-140 = +0.79 ± 0.12 and vehicle = +0.64 ± 0.10 mg/cm<sup>2</sup>/min), but no differences were noted with B2R antagonism. Protocol 2: pharmacological sweating was induced in 6 healthy subjects via intradermally perfusing pilocarpine (1.67 mg/mL) followed by the same B2R antagonist approach. Pilocarpine increased sweating (HOE-140 = +0.38 ± 0.16 and vehicle = +0.32 ± 0.12 mg/cm<sup>2</sup>/min); again no differences were observed with B2R antagonism. Last, 5 additional subjects were recruited for various control experiments which identified that a functional dose of HOE-140 was utilized and it was not sudorific during normothermic conditions. These data indicate B2R antagonists do not modulate physiologically or pharmacologically induced eccrine secretion volumes. Thus, B2R agonist/antagonist development as a potential therapeutic target for hypo- and hyperhidrosis appears unwarranted.

Sign in / Sign up

Export Citation Format

Share Document