Mast cells in type 2 skin inflammation: Maintenance and function

Keith, Yuki Honda; Egawa, Gyohei; Honda, Tetsuya; Kabashima, Kenji

doi:10.1002/eji.202250359

Cited by 10 publications

(4 citation statements)

References 102 publications

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“…An increase in MC in human and murine AD-like skin has been reported ( 10 , 67 , 68 ). MC releases several inflammatory cytokines that can interact with other immune and non-immune cells ( 69 , 70 ). MCP-1 is a chemokine that plays a significant role in facilitating the migration of monocytes, microglia, and memory T cells towards disruptions in the epidermal barrier and sites of inflammation ( 71 ).…”

Section: Discussionmentioning

confidence: 99%

MRGPRX2 antagonist GE1111 attenuated DNFB-induced atopic dermatitis in mice by reducing inflammatory cytokines and restoring skin integrity

Wong,

Choi,

et al. 2024

Front. Immunol.

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IntroductionAtopic dermatitis (AD) is a chronic inflammatory skin disorder characterised by itching, erythema, and epidermal barrier dysfunction. The pathogenesis of AD is complex and multifactorial; however,mast cell (MC) activation has been reported to be one of the crucial mechanisms in the pathogenesis of AD. The MC receptor Mas related G protein-coupled receptor-X2 (MRGPRX2) has been identified as a prominent alternative receptor to the IgE receptor in causing MC activation and the subsequent release of inflammatory mediators. The current study aimed to evaluate the therapeutic effect of a novel small molecule MRGPRX2 antagonist GE1111 in AD using in vitro and in vivo approaches. MethodsWe developed an in vitro cell culture disease model by using LAD-2 MC, HaCaT keratinocytes and RAW 264.7 macrophage cell lines. We challenged keratinocytes and macrophage cells with CST-14 treated MC supernatant in the presence and absence of GE1111 and measured the expression of tight junction protein claudin 1, inflammatory cytokines and macrophage phagocytosis activity through immunohistochemistry, western blotting, RT-qPCR and fluorescence imaging techniques. In addition to this, we developed a DFNB-induced AD model in mice and evaluated the protective effect and underlying mechanism of GE1111.Results and DiscussionOur in vitro findings demonstrated a potential therapeutic effect of GE1111, which inhibits the expression of TSLP, IL-13, MCP-1, TNF-a, and IL-1ß in MC and keratinocytes. In addition to this, GE1111 was able to preserve the expression of claudin 1 in keratinocytes and the phagocytotic activity of macrophage cells. The in vivo results demonstrated that GE1111 treatment significantly reduced phenotypic changes associated with AD (skin thickening, scaling, erythema and epidermal thickness). Furthermore, immunohistochemical analysis demonstrated that GE1111 treatment preserved the expression of the tight junction protein Involucrin and reduced the expression of the inflammatory mediator periostin in the mouse model of AD. These findings were supported by gene and protein expression analysis, where GE1111 treatment reduced the expression of TSLP, IL-13, and IL-1ß, as well as downstream signalling pathways of MRGPRX2 in AD skin lesions. In conclusion, our findings provide compelling in vitro and in vivo evidence supporting the contribution of MRGPRX2-MC interaction with keratinocytes and macrophages in the pathogenesis of AD.

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Section: Discussionmentioning

confidence: 99%

MRGPRX2 antagonist GE1111 attenuated DNFB-induced atopic dermatitis in mice by reducing inflammatory cytokines and restoring skin integrity

Wong,

Choi,

et al. 2024

Front. Immunol.

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“…Studies showed that growing numbers of mast cells in skin lesions contributed to the initiation of cutaneous inflammation in AD animal models and patients. 18,19 In this study, TB staining was employed to evaluate the infiltration of mast cells in the dermis (Figure 2B). Consistently, AD mice assembled more numbers of mast cells in the dorsal skin than normal mice (Figure 2D, p < 0.01).…”

Section: Effect Of Gos On Ad-like Clinical Phenotype In Dnfb-induced ...mentioning

confidence: 99%

Dietary Galacto-oligosaccharides Ameliorate Atopic Dermatitis-like Skin Inflammation and Behavioral Deficits by Modulating Gut Microbiota–Brain–Skin Axis

Tang,

Cao,

Chen

et al. 2024

J. Agric. Food Chem.

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Atopic dermatitis (AD), a chronic, highly pruritic, and inflammatory skin disorder, often coexists with psychiatric comorbidities including anxiety and depression, posing considerable challenges for treatment. The current research aims at evaluating the efficacy and potential therapeutic mechanism of galacto-oligosaccharides (GOS) on AD-like skin lesions and comorbid anxiety/depressive disorders. Macroscopical and histopathological examination showed that GOS could markedly relieve skin inflammation by decreasing the production of IgE, IL-4, IL-13, IFN-γ, and TNF-α and regulating the PPAR-γ/NF-κB signaling in DNFB-induced AD mice. Moreover, GOS significantly improved the anxiety- and depressive-like symptoms as mirrored by the behavior tests including FST, TST, OFT, and EZM through normalizing the neurotransmitter levels of 5-HT, DA, NE, and CORT in the brain. Mechanistically, by virtue of the high-throughput 16S rRNA gene sequencing and GC-MS techniques, GOS restructured the gut microbiota and specifically induced the proliferation of Lactobacillus and Alloprevotella, leading to an increase in the total content of fecal SCFAs, in particular acetate and butyrate. Pearson correlation analysis found a marked correlation among the altered gut microbiota/SCFAs, AD-associated skin manifestations, and comorbid behavioral phenotypes. Collectively, this work highlights that GOS is a promising strategy against both AD and associated depressive symptoms by modulating the gut microbiota-brain–skin axis.

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“…Lastly, it is important to appreciate the nuances in the murine models utilized to study dermatitis and the role of mast cells among these. Mast cells have been found to be largely dispensable in experimental models of AD using MC903 (calcipotriol, a vitamin D analog) 70 and acetone:ether-induced dry skin itch. 65 In simpatico with these, the sensation of itch in MC903-induced AD and acetone:ether-induced dry skin, was independent of Mrgprb2.…”

Section: Introductionmentioning

confidence: 99%