IL-33 is a new member of the IL-1 family that plays a role in allergic disease. In this study, we evaluated the potential on the inhibition of atopic dermatitis (AD) of anti-mouse IL-33 antibody (αIL-33Ab) using 2, 4-dinitrochlorobenzene (DNCB)-induced AD mice model. We treated mice with αIL-33Ab via subcutaneous injection of each DNCB treatment 1 h later from day 1 to day 33 for 14 times. A control group received tacrolimus. Skin lesion and scratching behavior were compared. Ear thickness, dermatitis score, eosinophils and mast cells infiltration, and serum IgE levels were also analyzed. Correlations between serum IL-33 as well as soluble(s) ST2 and AD disease activity index in human AD were also investigated. DNCB-induced AD-like mice treated with αIL-33Ab showed improved AD-like symptoms. Eosinophils and mast cells infiltration and serum IgE levels were also significantly reduced by αIL-33Ab. Our study suggests that blockade of IL-33 has a curative effect on AD.
Atopic dermatitis (AD) is a chronic inflammatory cutaneous disorder with few treatment options. Dynamin‐related protein 1 (Drp1)‐dependent mitochondrial fission contributes to the activation of NLRP3 inflammasome, and inhibiting Drp1 has been become an attractive therapeutic strategy for inflammatory diseases. This study aimed to investigate the effects of Drp1 inhibitor mdivi‐1 on experimental AD. We firstly detected the effects of mdivi‐1 on primary human keratinocytes in an inflammatory cocktail‐induced AD‐related inflammation in vitro. Results showed that mdivi‐1 inhibited NLRP3 inflammasome activation and pyroptosis which were evidenced by decreased expression of NLRP3, ASC, cleavage of caspase‐1, GSDMD‐NT, mature interleukin (IL)‐1β and IL‐18 in keratinocytes under AD‐like inflammation. Next, mouse model of AD‐like skin lesions was induced by epicutaneous application of 2,4‐dinitrochlorobenzene (DNCB) and mdivi‐1 (25 mg/kg/day, days 5–33 during construction of AD model) was intraperitoneally injected into DNCB‐induced mice. AD mice with mdivi‐1 treatment exhibited ameliorated AD symptoms, lower serum IgE level, and reduced epidermal thickening, mast cells infiltration, and production of IL‐4, IL‐5 and IL‐13 in the lesional tissues. Indeed, mdivi‐1 significantly inhibited NLRP3 inflammasome activation and pyroptotic injury occurred in DNCB‐treated skin tissues. Mechanically, mdivi‐1 regulated the expression of mitochondrial dynamic proteins and suppressed the activation of NF‐κB signal pathway which is an upstream of NLRP3 inflammasome both in vitro and in vivo. This study demonstrated that mdivi‐1 could protect against experimental AD through inhibiting the activation of NLRP3 inflammasome and subsequent inflammatory cytokine release, and mdivi‐1 might exert this function by inhibiting mitochondrial fission and subsequently blocking NF‐κB pathway.
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