Depletion of Gsdma1/2/3 alleviates PMA-induced epidermal hyperplasia by inhibiting the EGFR–Stat3/Akt pathway

Homeostasis of the skin barrier is essential for maintaining normal skin function.Gasdermin A(GSDMA)is highly expressed in the skin and associated with many skin diseases,such as melanoma and psoriasis.In mice,GSDMA is encoded by three gene homologues,namely Gsdma1,Gsdma2,and Gsdma3.Although Gsdma3 gain-of-function mutations cause hair loss and skin inflammation,Gsdma3-deficient mice do not show any visible phenotypes in skin and hair structures.To explore the physiological function of GSDMA,we generated conventional Gsdma1/2/3 knockout(KO)mice.These mice showed significantly alleviated epidermal hyperplasia and inflammation induced by phorbol 12-myristate 13-acetate(PMA).Furthermore,the alleviation of epidermal hyperplasia depended on the expression of Gsdma1/2/3 specifically in keratinocytes.Mechanistically,Gsdma1/2/3 depletion downregulated epidermal growth factor receptor(EGFR)ligands,leading to the decreased EGFR–Stat3/Akt signalling.These results demonstrate that depletion of Gsdma1/2/3 alleviates PMA-induced epidermal hyperplasia partially by inhibiting the EGFR–Stat3/Akt pathway.

The role of immune cells in obesogenic memory

Obesity is a serious chronic disease and worldwide public health problem.According to data from the World Health Organization(WHO),more than 650 million adults in the world were obese and three times more individuals were overweight in 2016.Obesity is associated with type II diabetes,hepatic steatosis,cardiovascular diseases,systemic chronic inflammation,and at least 13 types of cancer.Unfortunately,few effective remedies are available for obesity.The major problem is that most patients suffer from weight regain 2–3 years after obesity treatments,such as obesity drugs,lifestyle interventions(including exercise,diet restrictions,and diet modification),and bariatric surgery.Along with weight regain,most of the initial beneficial changes in metabolomic and transcriptomic profiles dissipate,including insulin sensitivity,the level of adipokines and blood cholesterol.This phenomenon has been defined as“obesogenic memory”.1,2 Obesogenic memory causes repeated weight loss and gain along with obesity therapy,which is called“weight cycling”,leading to a worse healthy status than would result from simple obesity.3,4.