A dysregulated sebum–microbial metabolite–IL-33 axis initiates skin inflammation in atopic dermatitis

Abstract

Microbial dysbiosis in the skin has been implicated in the pathogenesis of atopic dermatitis (AD); however, whether and how changes in the skin microbiome initiate skin inflammation, or vice versa, remains poorly understood. Here, we report that the levels of sebum and its microbial metabolite, propionate, were lower on the skin surface of AD patients compared with those of healthy individuals. Topical propionate application attenuated skin inflammation in mice with MC903-induced AD-like dermatitis by inhibiting IL-33 production in keratinocytes, an effect that was mediated through inhibition of HDAC and regulation of the AhR signaling pathway. Mice lacking sebum spontaneously developed AD-like dermatitis, which was improved by topical propionate application. A proof-of-concept clinical study further demonstrated the beneficial therapeutic effects of topical propionate application in AD patients. In summary, we have uncovered that the dysregulated sebum–microbial metabolite–IL-33 axis might play an initiating role in AD-related skin inflammation, thereby highlighting novel therapeutic strategies for the treatment of AD.

Sebaceous immunobiology - skin homeostasis, pathophysiology, coordination of innate immunity and inflammatory response and disease associations

“…Despite the dysfunctional synthesis of ceramides in keratinocytes ( 301 ) and the apparent skin xerosis in AD, the skin surface lipid concentration in patients with AD is marginally reduced but the proportion of sebaceous lipids is decreased and epidermal lipids (e.g. cholesterol) are increased ( 302 , 303 ), a fact that might initiate cytokine release and perifollicular inflammation.…”

“…Moreover, the antimicrobial proteins SPRR, whose synthesis and expression is abundant in the SG ( 27 ), were found to defend the skin permeability barrier by direct bacterial membrane disruption of the bacterial membrane ( 132 ). At last, sebaceous lipids, such as squalene ( 296 ) and propionic acid levels ( 303 ) are lower on the skin surface of AD patients compared with those of healthy individuals. In mice lacking sebum production with or without MC903-induced AD-like dermatitis, propionic acid attenuated skin inflammation ( 61 , 303 ).…”

“…At last, sebaceous lipids, such as squalene ( 296 ) and propionic acid levels ( 303 ) are lower on the skin surface of AD patients compared with those of healthy individuals. In mice lacking sebum production with or without MC903-induced AD-like dermatitis, propionic acid attenuated skin inflammation ( 61 , 303 ). Propionic acid reduced skin inflammation by inhibiting IL33 production in keratinocytes, an effect that was mediated through inhibition of histone deacetylase (HDAC) and regulation of the AhR signaling pathway ( 303 ).…”

“…In mice lacking sebum production with or without MC903-induced AD-like dermatitis, propionic acid attenuated skin inflammation ( 61 , 303 ). Propionic acid reduced skin inflammation by inhibiting IL33 production in keratinocytes, an effect that was mediated through inhibition of histone deacetylase (HDAC) and regulation of the AhR signaling pathway ( 303 ). A proof-of-concept clinical study further demonstrated the beneficial therapeutic effects of topical propionic acid application in AD patients ( 303 ).…”

Involvement of Atopic Dermatitis in the Development of Systemic Inflammatory Diseases

“…The skin is recognized as a peripheral lymphoid tissue located in the most layered organ and is influenced by external environments [ 7 , 8 ]. Environmental stimuli and pathogens that are exposed to the skin cause various physiological and pathological reactions [ 9 , 10 ]. Chronic inflammation is a representative response to these environmental stimuli, and repeated exposure to external pathogens [ 11 , 12 ].…”