SFPQ/S100A8 complex induces filaggrin deficiency via selective autophagy and JNK phosphorylation in atopic dermatitis

Although atopic dermatitis (AD) is associated with a decrease of filaggrin levels, the underlying mechanisms are not clearly understood. Here, we aimed to investigate the pathogenic roles of the splicing factor proline- and glutamine-rich (SFPQ)/S100 calcium-binding protein A8 (S100A8) complex, a critical regulator inducing filaggrin deficiency in AD. The formation of SFPQ/S100A8 complex was analyzed in the keratinocytes and skin tissues from patients with AD and 2,4-dinitrochlorobenzene (DNCB)-induced AD-like mice. The effects of leptomycin B, a CRM1 inhibitor, and rapamycin, a mTOR inhibitor were determined in DNCB-induced AD-like mice and the non-lesional and lesional primary keratinocytes of AD patients. The relocation of SFPQ from the nucleus to the cytoplasm, elevated S100A8 levels, and SFPQ/S100A8 complex formation were proportional to filaggrin deficiency and AD severity in the keratinocytes of AD patients and AD-like mice. Interaction of the complex with filaggrin and c-Jun N-terminal kinase (JNK) accelerated filaggrin degradation via selective autophagy and filaggrin downregulation via JNK phosphorylation, respectively. The mechanistic target of rapamycin kinase (mTOR) and chromosomal region maintenance 1 (CRM1) facilitated the cytosolic export of SFPQ to form the complex in human keratinocytes. Administration of leptomycin B and rapamycin suppressed the decrease in filaggrin levels by inhibiting SFPQ/S100A8 complex formation in AD-like mice. This study demonstrates that the formation of SFPQ/S100A8 complex is a critical process in AD progression, which provides key insights into the pathogenic mechanisms of AD. The elucidation of the SFPQ/S100A8 complex axis in AD pathogenesis can be leveraged to develop therapeutic drugs for AD treatment.