Signal Transducer and Activator of Transcription 6 Is Essential in the Induction of Contact Hypersensitivity

Annexin A1 (AnxA1) is recognized as an endogenous anti-inflammatory molecule. However, its effects on the adaptive immune response and, in particular, on T cells remain unclear. In this study, we investigated the actions of AnxA1 in three distinct models of T cell–mediated inflammation. In contact hypersensitivity, collagen-induced arthritis, and inflammation induced by OT-II TCR transgenic T cells responding to OVA, AnxA1 deficiency significantly increased Ag-induced T cell proliferation and the resultant level of inflammation. In the contact hypersensitivity model, this was associated with increased adhesion of CD4+ T cells, CD8+ T cells, and neutrophils in the dermal microvasculature, as well as increased T cell expression of RORγt and IL-17A. In collagen-induced arthritis, deficiency of endogenous AnxA1 increased susceptibility to arthritis and Ag-specific T cell activation. Deficiency of AnxA1 also increased OVA-induced cutaneous delayed-type hypersensitivity and IFN-γ and IL-17 release. Transfer experiments using CD4+ T cells from AnxA1−/− mice demonstrated that the absence of AnxA1 solely in T cells resulted in increased inflammatory responses in wild-type recipients. Similarly, experiments using AnxA1−/− OT-II CD4+ T cells demonstrated that the absence of AnxA1 in T cells was sufficient to induce increased Ag-specific CD4+ T cell proliferation in vivo, augment T cell production of IFN-γ, IL-17, TNF, and IL-6, and increase Akt, ERK, and p38 activation. Together, these findings indicate that T cell–expressed AnxA1 functions to attenuate T cell–driven inflammatory responses via T cell–intrinsic effects on intracellular signaling, proliferation, and Th1/Th17 cytokine release.

Section: Discussionmentioning

confidence: 99%

Deficiency of Annexin A1 in CD4+ T Cells Exacerbates T Cell–Dependent Inflammation

Yang

Song

Deane

et al. 2013

“…In mouse models of allergic lung inflammation (41)(42)(43), contact hypersensitivity (44), and allergic diarrhea (45), STAT6 deficiency was accompanied by a lack of eosinophil influx into the sites of allergic inflammation. This effect may be at least partially due to defective eotaxin-1 production in these animals.…”

Section: Discussionmentioning

confidence: 99%

STAT6 Mediates Eotaxin-1 Expression in IL-4 or TNF-α-Induced Fibroblasts

Hoeck

Woisetschläger

2001

127

137

Eosinophils are attracted to sites of allergic inflammation by a number of chemoattractants including eotaxin-1. This chemokine can be secreted from epithelial cells and fibroblasts after IL-4 and TNF-α stimulation in a synergistic fashion. TNF-α activated gene expression at the transcriptional level in a STAT6-dependent manner, because: 1) eotaxin-1 promoter luciferase constructs were TNF-α inducible in STAT6-defective HEK293 cells only on cotransfection of STAT6 expression vector, an effect that was partially mediated by activation-induced binding of NF-κB proteins to a composite STAT6/NF-κB element; 2) reporter constructs defective in STAT6 DNA binding did not respond to TNF-α stimulation; 3) eotaxin-1 protein secretion was detected only in STAT6-transfected HEK293 cell supernatants on TNF-α treatment; and 4) a trans-dominant negative STAT6 protein inhibited TNF-α-induced eotaxin-1 secretion in primary fibroblasts. TNF-α inducibility of the IL-8 and monocyte chemoattractant protein-1 genes was not dependent on STAT6 expression in the same experimental systems. The inducing effect of IL-4 and IL-13 was also mediated by STAT6. The synergistic effect of IL-4 and TNF-α observed at the RNA and the protein level was not seen at the promoter level. The data demonstrate that both IL-4 and TNF-α induce eotaxin-1 expression at the level of transcription via a STAT6-mediated pathway.

“…Trinitrophenyl (TNP)-specific IgE (TNP-IgE)-transgenic (TNP-IgE-Tg) mice (21) (BALB/c background) were kindly provided by Dr. Hajime Karasuyama (Department of Immune Regulation, Tokyo Medical and Dental University). STAT6-deficient mice (STAT6 2/2 ) (C57BL/6 background) were described previously (23,24). Mice were maintained under specific pathogen-free conditions in our animal facility.…”

Section: Micementioning

confidence: 99%

Protective Role of STAT6 in Basophil-Dependent Prurigo-like Allergic Skin Inflammation

Hashimoto

Satoh

Yokozeki

2015

Self Cite

Prurigo is a common, but treatment-resistant, skin disease characterized by persistent papules/nodules and severe itching. Prurigo occurs in association with various underlying diseases, such as diabetes, chronic renal failure, and internal malignancies. Atopic dermatitis is occasionally complicated by prurigo lesions. However, the pathology of prurigo is completely undefined. We demonstrate that repeated intradermal administration of Ag to IgE-transgenic mice causes persistent and pruritic papulonodular skin lesions mimicking prurigo. Skin lesions were histopathologically characterized by irregular acanthosis and dermal cellular infiltrates comprising eosinophils, mononuclear cells, and basophils, with epidermal nerve fiber sprouting. In vivo depletion of basophils alleviated skin reactions, indicating that the inflammation is basophil dependent. Unexpectedly, STAT6 signaling was unnecessary for skin lesion development if IgE was present. Moreover, the absence of STAT6 signaling exacerbated the inflammation, apparently as the result of impaired generation of an M2-type anti-inflammatory macrophage response. These results provide novel insights into the pathologic mechanisms underlying prurigo. Although basophils are indispensable for prurigo-like inflammation, Th2 immunity mediated by STAT6 appears to play a protective role, and therapies targeting Th2-type cytokines may risk aggravating the inflammation.