Roles of Epithelial Cell–Derived Type 2–Initiating Cytokines in Experimental Allergic Conjunctivitis

Asada, Yosuke; Nakae, Susumu; Ishida, Waka; Hori, Kanji; Sugita, Jobu; Sudo, Katsuko; Fukuda, Ken; Fukushima, Atsuki; Suto, Hajime; Murakami, Akira; Saito, Hirohisa; Ebihara, Nobuyuki; Matsuda, Akira

doi:10.1167/iovs.15-16563

Cited by 19 publications

(22 citation statements)

References 34 publications

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“…Our results showed the indispensable roles of IL‐33 and TSLP in the eosinophil infiltration induced by papain‐CL, this result is consistent with previous reports showing attenuated papain‐induced allergic airway inflammation in IL‐33 KO mice , and reduced papain‐induced allergic inflammation in the lung of TSLPR KO mice . In the case of ragweed induced experimental allergic conjunctivitis, we evaluated clinical scores (lid edema, conjunctival hyperemia, and swelling) as parameters to grade severity of inflammation . However, in the case of papain‐CL model, it was difficult to obtain reliable clinical scores because the inflammation of this model did not highly depend on immediate hypersensitivity reactions.…”

Section: Discussionsupporting

confidence: 91%

“…The cytokines are produced and released from epithelial cells in response to allergens, parasites, and tissue damage. Recently, we investigated the roles of type 2 immune response-initiating cytokines in ragweed-induced experimental allergic conjunctivitis (ragweed EAC) using IL-33-, IL-25-, and TSLP receptor (TSLPR)-knockout (KO) mice [4]. We found attenuated eosinophil infiltration and reduced Th2 cytokine (il4, il5, and il13) mRNA expression in the ragweed EAC model using IL-33 KO mice, suggesting an indispensable role for IL-33 in the pathophysiology of ragweed EAC mostly driven by adaptive immune responses [5].…”

Section: Introductionmentioning

confidence: 99%

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Contributions of Interleukin‐33 and TSLP in a papain‐soaked contact lens‐induced mouse conjunctival inflammation model

Sugita

Asada

Ishida

et al. 2017

Immunity Inflam & Disease

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IntroductionPathological changes of severe chronic allergic conjunctivitis are driven not only via acquired immunity but also via innate immunity. Type 2 immune response‐initiating cytokines may play some roles as innate immunity‐dependent components of the ocular surface inflammation. To investigate the involvement of type 2 immune response‐initiating cytokines in innate immunity‐dependent, papain‐induced conjunctival inflammation model using IL‐25‐, IL‐33‐, and TSLP receptor (TSLPR)‐knockout (KO) mice with reference to basophils and ILC2.MethodsPapain‐soaked contact lenses (papain‐CLs) were installed in the conjunctival sacs of C57BL/6‐IL‐25 KO, IL‐33 KO, TSLPR KO, Rag2 KO, Bas‐TRECK, and wild‐type mice and their eyes were sampled at day 5. The eosinophil and basophil infiltration in papain‐CL model was evaluated histologically and cytokine expression was examined. To clarify the roles of basophils and ILC2, basophil/ILC2‐depletion experiments were carried out.ResultsPapain‐induced conjunctival inflammation exhibited eosinophil infiltration and upregulation of Th2 cytokine expression. Reduction of eosinophil and basophil infiltration and attenuated Th2 cytokine expression were observed in the papain‐CL model using IL‐33 KO and TSLPR KO mice. Depletion of basophils or ILC2s in the conjunctivae of the papain‐CL model reduced eosinophil infiltration.ConclusionsInnate immunity‐driven type 2 immune responses of the ocular surface are dependent on IL‐33, TSLP, basophils, and ILC2. These components may be possible therapeutic targets for refractory allergic keratoconjunctivitis.

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Section: Discussionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Contributions of Interleukin‐33 and TSLP in a papain‐soaked contact lens‐induced mouse conjunctival inflammation model

Sugita

Asada

Ishida

et al. 2017

Immunity Inflam & Disease

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“…IL-33 has been now recognized to trigger asthma, rhinitis, atopic dermatitis and allergic conjunctivitis68910. Recently, the role of IL-33 in initiating allergic inflammation has been investigated in SRW pollen-induced mouse models of allergic conjunctivitis1112 or allergic rhinitis13. The studies of Asada and Haenuki were carried out using IL-33 knockout mice and showed the pathophysiological roles of IL-33 in SRW induced allergic disease models in mouse1213.…”

mentioning

confidence: 99%

“…Recently, the role of IL-33 in initiating allergic inflammation has been investigated in SRW pollen-induced mouse models of allergic conjunctivitis1112 or allergic rhinitis13. The studies of Asada and Haenuki were carried out using IL-33 knockout mice and showed the pathophysiological roles of IL-33 in SRW induced allergic disease models in mouse1213. However, it remains unknown whether and how IL-33 is induced by pollen allergens via TLR4-dependent innate immunity pathways.…”

mentioning

confidence: 99%

Pollen/TLR4 Innate Immunity Signaling Initiates IL-33/ST2/Th2 Pathways in Allergic Inflammation

Jin

Zhang

Chen

et al. 2016

Sci Rep

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Innate immunity has been extended to respond environmental pathogen other than microbial components. Here we explore a novel pollen/TLR4 innate immunity in allergic inflammation. In experimental allergic conjunctivitis induced by short ragweed (SRW) pollen, typical allergic signs, stimulated IL-33/ST2 signaling and overproduced Th2 cytokine were observed in ocular surface, cervical lymph nodes and isolated CD4+ T cells of BALB/c mice. These clinical, cellular and molecular changes were significantly reduced/eliminated in TLR4 deficient (Tlr4-d) or MyD88 knockout (MyD88−/−) mice. Aqueous SRW extract (SRWe) directly stimulated IL-33 mRNA and protein expression by corneal epithelium and conjunctiva in wild type, but not in Tlr4-d or MyD88−/− mice with topical challenge. Furthermore, SRWe-stimulated IL-33 production was blocked by TLR4 antibody and NF-kB inhibitor in mouse and human corneal epithelial cells. These findings for the first time uncovered a novel mechanism by which SRW pollen initiates TLR4-dependent IL-33/ST2 signaling that triggers Th2-dominant allergic inflammation.

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“…After ragweed pollen administration, IL-33 is released and lead to the infiltration of eosinophils and CD4 + T cells with activated ST2 on the surface in conjunctival stroma [ 110 ]. These activations are obviously reduced in IL-33-knockout mice [ 111 ]. Furthermore, pollen-induced IL-33 production is decreased in TLR4-deficient mice and is blocked by TLR4 antibody in vitro [ 112 ].…”

Section: The Role Of Il-33 In Allergic Diseasesmentioning

confidence: 99%

Interleukin-33: Its Emerging Role in Allergic Diseases

et al. 2018

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Allergic diseases, which include asthma, allergic rhinitis (AR), chronic rhinosinusitis (CRS), atopic dermatitis (AD), food allergy (FA), allergic keratoconjunctivitis, seriously affect the quality of life of people all over the world. Recently, interleukin-33 (IL-33) has been found to play an important role in these refractory disorders, mainly by inducing T helper (Th) 2 immune responses. This article reviews the mobilization and biological function of IL-33 in allergic disorders, providing novel insights for addressing these hypersensitive conditions.

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Roles of Epithelial Cell–Derived Type 2–Initiating Cytokines in Experimental Allergic Conjunctivitis

Abstract: Among the type 2-initiating cytokines, IL-33 may play a major role in conjunctival inflammation in an RW-EAC model.

Cited by 19 publications

References 34 publications

Contributions of Interleukin‐33 and TSLP in a papain‐soaked contact lens‐induced mouse conjunctival inflammation model

Contributions of Interleukin‐33 and TSLP in a papain‐soaked contact lens‐induced mouse conjunctival inflammation model

Pollen/TLR4 Innate Immunity Signaling Initiates IL-33/ST2/Th2 Pathways in Allergic Inflammation

Interleukin-33: Its Emerging Role in Allergic Diseases

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