Interleukin‐37 inhibits desmoglein‐3 endocytosis and keratinocyte dissociation via upregulation of Caveolin‐1 and inhibition of the STAT3 pathway

Abstract Background Pemphigus vulgaris (PV) is a potentially fatal autoimmune bullous disease primarily caused by acantholysis of keratinocytes attributed to pathogenic desmoglein‐3 (Dsg3) autoantibodies. Interleukin‐37 (IL‐37) reportedly plays important roles in a variety of autoimmune diseases, but its role in PV is not clear. Objectives To investigate whether IL‐37 plays a role in the occurrence and progression of PV. Methods HaCaT keratinocytes were stimulated with anti‐Dsg3 antibody to establish an in vitro PV model, which was defined as anti‐Dsg3 group. Cells incubated with medium without anti‐Dsg3 treatment were used as control. IL‐37 was cultured with these cells infected with or without lentiviral vector shRNA‐Caveolin‐1 (sh‐Cav‐1‐LV). Cell dissociation assay and immunocytofluorescence were performed to assess keratinocyte dissociation, keratin retraction and Dsg3 endocytosis. Real‐time PCR was used to detect the mRNA level of Cav‐1, and western blot was used to determine the protein expression of Cav‐1, Dsg3, STAT3 and phosphorylated‐STAT3 (p‐STAT3). Results The anti‐Dsg3 group showed more cell debris, increased keratin retraction, increased Dsg3 endocytosis, reduced Cav‐1 expression and co‐localization than the control group, while IL‐37 treatment neutralized all of these changes. Interestingly, Cav‐1 knockdown supressed the inhibitory effect of IL‐37 on keratinocyte dissociation and Dsg3 internalization. The protein expression of p‐STAT3 was increased in keratinocytes of the PV model but decreased by IL‐37. Re‐activation of the STAT3 pathway by colivelin supressed the inhibitory effect of IL‐37 on keratinocyte dissociation and Dsg3 internalization, along with upregulation of Cav‐1 and Dsg3. Conclusions IL‐37 inhibited keratinocyte dissociation and Dsg3 endocytosis in an in vitro PV model through the upregulating Cav‐1 and inhibiting STAT3 pathway.