scholarly journals Pruritus as a Distinctive Feature of Type 2 Inflammation

Vaccines ◽  
2021 ◽  
Vol 9 (3) ◽  
pp. 303
Author(s):  
Simone Garcovich ◽  
Martina Maurelli ◽  
Paolo Gisondi ◽  
Ketty Peris ◽  
Gil Yosipovitch ◽  
...  
Keyword(s):  
Lupus Erythematosus ◽  
Skin Diseases ◽  
Skin Surface ◽  
Lymphoid Cells ◽  
Common Symptom ◽  
Prurigo Nodularis ◽  
Chronic Itch ◽  
Type 2 Cytokines ◽  
Type 2 Inflammation

Pruritus is a common symptom of several skin diseases, both inflammatory and neoplastic. Pruritus might have a tremendous impact on patients’ quality of life and strongly interfere with sleep, social, and work activities. We review the role of type-2 inflammation and immunity in the pathogenesis of chronic pruritic conditions of the skin. Type 2 cytokines, including IL-4, IL-13, thymic stromal lymphopoietin, periostin, IL-31, IL-25, and IL-33 are released by mast cells, innate lymphoid cells 2, keratinocytes, and type 2 T lymphocytes, and are master regulators of chronic itch. These cytokines might act as direct pruritogen on primary sensory neurons (pruriceptors) or alter the sensitivity to other itch mediators Type 2 inflammation- and immunity-dominated skin diseases, including atopic dermatitis, prurigo nodularis, bullous pemphigoid, scabies, parasitic diseases, urticaria, and Sézary syndrome are indeed conditions associated with most severe pruritus. In contrast, in other skin diseases, such as scleroderma, lupus erythematosus, hidradenitis suppurativa, and acne, type 2 inflammation is less represented, and pruritus is milder or variable. Th2 inflammation and immunity evolved to protect against parasites, and thus, the scratching response evoked by pruritus might have developed to alert about the presence and to remove parasites from the skin surface.

scholarly journals The CysLT2R receptor mediates leukotriene C4-driven acute and chronic itch

2021 ◽  
Vol 118 (13) ◽  
pp. e2022087118
Author(s):  
Tiphaine Voisin ◽  
Caroline Perner ◽  
Marie-Angele Messou ◽  
Stephanie Shiers ◽  
Saltanat Ualiyeva ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Skin Diseases ◽  
Chronic Phase ◽  
Drg Neurons ◽  
Dry Skin ◽  
Chronic Itch ◽  
Allergic Skin ◽  
Dose Dependent ◽  
Type 2 Inflammation

Acute and chronic itch are burdensome manifestations of skin pathologies including allergic skin diseases and atopic dermatitis, but the underlying molecular mechanisms are not well understood. Cysteinyl leukotrienes (CysLTs), comprising LTC4, LTD4, and LTE4, are produced by immune cells during type 2 inflammation. Here, we uncover a role for LTC4 and its signaling through the CysLT receptor 2 (CysLT2R) in itch. Cysltr2 transcript is highly expressed in dorsal root ganglia (DRG) neurons linked to itch in mice. We also detected CYSLTR2 in a broad population of human DRG neurons. Injection of leukotriene C4 (LTC4) or its nonhydrolyzable form NMLTC4, but neither LTD4 nor LTE4, induced dose-dependent itch but not pain behaviors in mice. LTC4-mediated itch differed in bout duration and kinetics from pruritogens histamine, compound 48/80, and chloroquine. NMLTC4-induced itch was abrogated in mice deficient for Cysltr2 or when deficiency was restricted to radioresistant cells. Itch was unaffected in mice deficient for Cysltr1, Trpv1, or mast cells (WSh mice). CysLT2R played a role in itch in the MC903 mouse model of chronic itch and dermatitis, but not in models of dry skin or compound 48/80- or Alternaria-induced itch. In MC903-treated mice, CysLT levels increased in skin over time, and Cysltr2−/− mice showed decreased itch in the chronic phase of inflammation. Collectively, our study reveals that LTC4 acts through CysLT2R as its physiological receptor to induce itch, and CysLT2R contributes to itch in a model of dermatitis. Therefore, targeting CysLT signaling may be a promising approach to treat inflammatory itch.

Prominent Role of Type 2 Immunity in Skin Diseases—Beyond Atopic Dermatitis

2021 ◽  
pp. 120347542110278
Author(s):  
Lina Belmesk ◽  
Anastasiya Muntyanu ◽  
Emmanuelle Cantin ◽  
Zeinah AlHalees ◽  
Carolyn S. Jack ◽  
...  
Keyword(s):  
Atopic Dermatitis ◽  
Cancer Progression ◽  
Skin Diseases ◽  
Skin Neoplasms ◽  
Lymphoid Cells ◽  
Type 2 Immunity ◽  
Group 2 ◽  
Type 2 Inflammation

Type 2 immunity, illustrated by T helper 2 lymphocytes (Th2) and downstream cytokines (IL-4, IL-13, IL-31) as well as group 2 innate lymphoid cells (ILC2), is important in host defense and wound healing. 1 The hallmark of type 2 inflammation is eosinophilia and/or high IgE counts and is best recognized in atopic diathesis. Persistent eosinophilia, such as seen in hypereosinophilic syndromes, leads to fibrosis and hence therapeutic Type 2 inhibition in fibrotic diseases is of high interest. Furthermore, as demonstrated in cutaneous T cell lymphoma, advanced disease is characterized by Th1 to Th2 switch allowing cancer progression and immunosuppression. Development of targeted monoclonal antibodies against IL-4Rα (eg, dupilumab) led to a paradigm shift for the treatment of atopic dermatitis (AD) and stimulated research to better understand the role of Type 2 inflammation in other skin conditions. In this review, we summarize up to date knowledge on the role of Type 2 inflammation in skin diseases other than AD and highlight whether the use of Type 2 targeted therapies has been documented or is being investigated in clinical trials. This manuscript reviews the role of Type 2 inflammation in dermatitis, neurodermatitis, IgE-mediated dermatoses (eg, bullous pemphigoid, chronic spontaneous urticaria), sclerodermoid conditions and skin neoplasms.

scholarly journals Maintenance of Type 2 Response by CXCR6-Deficient ILC2 in Papain-Induced Lung Inflammation

2019 ◽  
Vol 20 (21) ◽  
pp. 5493 ◽  
Author(s):  
Meunier ◽  
Chea ◽  
Garrido ◽  
Perchet ◽  
Petit ◽  
...  
Keyword(s):  
Immune Response ◽  
Immune Responses ◽  
Nk Cell ◽  
Lymphoid Cells ◽  
Inflammatory Conditions ◽  
Airway Diseases ◽  
Type 2 Cytokines ◽  
Lymphoid Organogenesis ◽  
Deficient Mice

Innate lymphoid cells (ILC) are important players of early immune defenses in situations like lymphoid organogenesis or in case of immune response to inflammation, infection and cancer. Th1 and Th2 antagonism is crucial for the regulation of immune responses, however mechanisms are still unclear for ILC functions. ILC2 and NK cells were reported to be both involved in allergic airway diseases and were shown to be able to interplay in the regulation of the immune response. CXCR6 is a common chemokine receptor expressed by all ILC, and its deficiency affects ILC2 and ILC1/NK cell numbers and functions in lungs in both steady-state and inflammatory conditions. We determined that the absence of a specific ILC2 KLRG1+ST2– subset in CXCR6-deficient mice is probably dependent on CXCR6 for its recruitment to the lung under inflammation. We show that despite their decreased numbers, lung CXCR6-deficient ILC2 are even more activated cells producing large amount of type 2 cytokines that could drive eosinophilia. This is strongly associated to the decrease of the lung Th1 response in CXCR6-deficient mice.

scholarly journals Pulmonary environmental cues drive group 2 innate lymphoid cell dynamics in mice and humans

2019 ◽  
Vol 4 (36) ◽  
pp. eaav7638 ◽  
Author(s):  
Franz Puttur ◽  
Laura Denney ◽  
Lisa G. Gregory ◽  
Juho Vuononvirta ◽  
Robert Oliver ◽  
...  
Keyword(s):  
Chemokine Receptors ◽  
Lymphoid Cells ◽  
Perivascular Spaces ◽  
Cell Dynamics ◽  
Mucosal Tissues ◽  
Migratory Patterns ◽  
Group 2 ◽  
Environmental Exploration ◽  
Type 2 Inflammation

Group 2 innate lymphoid cells (ILC2s) are enriched in mucosal tissues (e.g., lung) and respond to epithelial cell–derived cytokines initiating type 2 inflammation. During inflammation, ILC2 numbers are increased in the lung. However, the mechanisms controlling ILC2 trafficking and motility within inflamed lungs remain unclear and are crucial for understanding ILC2 function in pulmonary immunity. Using several approaches, including lung intravital microscopy, we demonstrate that pulmonary ILC2s are highly dynamic, exhibit amoeboid-like movement, and aggregate in the lung peribronchial and perivascular spaces. They express distinct chemokine receptors, including CCR8, and actively home to CCL8 deposits located around the airway epithelium. Within lung tissue, ILC2s were particularly motile in extracellular matrix–enriched regions. We show that collagen-I drives ILC2 to markedly change their morphology by remodeling their actin cytoskeleton to promote environmental exploration critical for regulating eosinophilic inflammation. Our study provides previously unappreciated insights into ILC2 migratory patterns during inflammation and highlights the importance of environmental guidance cues in the lung in controlling ILC2 dynamics.

scholarly journals TNF Induces the Production of Type 2 Cytokines in Human Group 2 Innate Lymphoid Cells

2019 ◽  
Vol 143 (2) ◽  
pp. AB1
Author(s):  
Atsushi Kato ◽  
Noriko Ogasawara ◽  
Julie A. Poposki ◽  
Aiko I. Klingler ◽  
Kathryn E. Hulse ◽  
...  
Keyword(s):  
Innate Lymphoid Cells ◽  
Lymphoid Cells ◽  
Human Group ◽  
Type 2 Cytokines ◽  
Group 2

scholarly journals IL-10 Prevents the Production of Type 2 Cytokines in Human Group 2 Innate Lymphoid Cells

2017 ◽  
Vol 139 (2) ◽  
pp. AB14
Author(s):  
Noriko Ogasawara ◽  
Julie A. Poposki ◽  
Aiko I. Klingler ◽  
Bruce K. Tan ◽  
Kathryn E. Hulse ◽  
...  
Keyword(s):  
Innate Lymphoid Cells ◽  
Lymphoid Cells ◽  
Human Group ◽  
Type 2 Cytokines ◽  
Group 2

scholarly journals A role for IL-25 and IL-33–driven type-2 innate lymphoid cells in atopic dermatitis

2013 ◽  
Vol 210 (13) ◽  
pp. 2939-2950 ◽  
Author(s):  
Maryam Salimi ◽  
Jillian L. Barlow ◽  
Sean P. Saunders ◽  
Luzheng Xue ◽  
Danuta Gutowska-Owsiak ◽  
...  
Keyword(s):  
Atopic Dermatitis ◽  
Mouse Skin ◽  
Allergen Challenge ◽  
Atopic Disease ◽  
Innate Lymphoid Cells ◽  
Lymphoid Cells ◽  
Type 2 Cytokines ◽  
Skin Homing ◽  
E Cadherin

Type 2 innate lymphoid cells (ILC2s, nuocytes, NHC) require RORA and GATA3 for their development. We show that human ILC2s express skin homing receptors and infiltrate the skin after allergen challenge, where they produce the type 2 cytokines IL-5 and IL-13. Skin-derived ILC2s express the IL-33 receptor ST2, which is up-regulated during activation, and are enriched in lesional skin biopsies from atopic patients. Signaling via IL-33 induces type 2 cytokine and amphiregulin expression, and increases ILC2 migration. Furthermore, we demonstrate that E-cadherin ligation on human ILC2 dramatically inhibits IL-5 and IL-13 production. Interestingly, down-regulation of E-cadherin is characteristic of filaggrin insufficiency, a cardinal feature of atopic dermatitis (AD). ILC2 may contribute to increases in type 2 cytokine production in the absence of the suppressive E-cadherin ligation through this novel mechanism of barrier sensing. Using Rag1−/− and RORα-deficient mice, we confirm that ILC2s are present in mouse skin and promote AD-like inflammation. IL-25 and IL-33 are the predominant ILC2-inducing cytokines in this model. The presence of ILC2s in skin, and their production of type 2 cytokines in response to IL-33, identifies a role for ILC2s in the pathogenesis of cutaneous atopic disease.

scholarly journals The neuropeptide neuromedin U stimulates innate lymphoid cells and type 2 inflammation

Nature ◽  
2017 ◽  
Vol 549 (7671) ◽  
pp. 282-286 ◽  
Author(s):  
Christoph S. N. Klose ◽  
Tanel Mahlakõiv ◽  
Jesper B. Moeller ◽  
Lucille C. Rankin ◽  
Anne-Laure Flamar ◽  
...  
Keyword(s):  
Innate Lymphoid Cells ◽  
Lymphoid Cells ◽  
Type 2 Inflammation

scholarly journals Immunization with Leishmania major Exogenous Antigens Protects Susceptible BALB/c Mice against Challenge Infection with L. major

2004 ◽  
Vol 72 (10) ◽  
pp. 5654-5661 ◽  
Author(s):  
Willy K. Tonui ◽  
J. Santiago Mejia ◽  
Lisa Hochberg ◽  
M. Lamine Mbow ◽  
Jeffrey R. Ryan ◽  
...  
Keyword(s):  
Western Blot ◽  
Leishmania Major ◽  
Challenge Infection ◽  
Lymphoid Cells ◽  
Interleukin 12 ◽  
Protective Response ◽  
Type 2 Cytokines

ABSTRACT The potential of Leishmania major culture-derived soluble exogenous antigens (SEAgs) to induce a protective response in susceptible BALB/c mice challenged with L. major promastigotes was investigated. Groups of BALB/c mice were immunized with L. major SEAgs alone, L. major SEAgs coadministered with either alum (aluminum hydroxide gel) or recombinant murine interleukin-12 (rmIL-12), L. major SEAgs coadministered with both alum and rmIL-12, and L. major SEAgs coadministered with Montanide ISA 720. Importantly and surprisingly, the greatest and most consistent protection against challenge with L. major was seen in mice immunized with L. major SEAgs alone, in the absence of any adjuvant. Mice immunized with L. major SEAgs had significantly smaller lesions that at times contained more than 100-fold fewer parasites. When lymphoid cells from L. major SEAg-immunized mice were stimulated with leishmanial antigen in vitro, they proliferated and secreted a mixed profile of type 1 and type 2 cytokines. Finally, analyses with Western blot analyses and antibodies against three surface-expressed and secreted molecules of L. major (lipophosphoglycan, gp46/M2/PSA-2, and gp63) revealed that two of these molecules are present in L. major SEAgs, lipophosphoglycan and the molecules that associate with it and gp46/M2/PSA-2.

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