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

Abstract

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.

STAT6 deficiency ameliorates Graves' disease severity by suppressing thyroid epithelial cell hyperplasia

“…p-STAT6 is closely related to epithelial cell hyperplasia, which is the cause of ulcerative colitis, lung inflammation and skin inflammation. [11][12][13] To investigate whether p-STAT6 plays a similar role in GD, we first explored p-STAT6 expression in TECs from GD patients and control individuals.…”

New insights into basophil heterogeneity

“…In line with its ability to down-regulate FcεRI, these patients respond to treatment with omalizumab therapy [70,79]. Further, we would predict in this setting that IL-3-elicited basophils are the primary pathogenic basophil subset since basophils are known to be critical for the pathogenesis of IgE-mediated dermatitis in mice [19,80–82]. Whether omalizumab can improve outcomes in other IgE- and basophil-associated diseases such as food allergy is currently under investigation [83].…”

“…2) [81,82,144]. Macrophages undergo alternative activation in the presence of IL-4 or IL-13 which is characterized by increased expression of signature genes including Arginase-I, chitinase-like molecules and resistin-like molecule α (Relmα).…”

“…Alternatively activated macrophages (referred to as M2 macrophages) are classically believed to be anti-inflammatory in function and also increase their surface expression of CD206, CD301, MHC class II molecules and PD-L2 [144–148]. Basophils, as a potent source of IL-4, are critical for M2 macrophage polarization in allergic and infectious settings in a STAT6-dependent manner [81,82,149]. Indeed, recent studies employing an IgE-dependent model of chronic allergic dermatitis demonstrated that basophil-derived IL-4 plays a key role in the differentiation of Ccr2 + monocytes in the skin to anti-inflammatory M2 macrophages to dampen skin inflammation [81,82].…”

“…Basophils, as a potent source of IL-4, are critical for M2 macrophage polarization in allergic and infectious settings in a STAT6-dependent manner [81,82,149]. Indeed, recent studies employing an IgE-dependent model of chronic allergic dermatitis demonstrated that basophil-derived IL-4 plays a key role in the differentiation of Ccr2 + monocytes in the skin to anti-inflammatory M2 macrophages to dampen skin inflammation [81,82]. The recruitment of monocytes was found to be critically dependent on Ccr2, which has several ligands including Ccl2, Ccl7 and Ccl12 [150].…”