Ablation of the deubiquitinating enzyme cylindromatosis (CYLD) augments STAT1-mediated M1 macrophage polarization and fosters control.

In atopic dermatitis (AD), lesional skin is frequently colonized by , which promotes clinical symptoms of the disease. The inflammatory milieu in the skin is characterized by a Th2 response, including M2 macrophages, which cannot eradicate . Therefore, repolarization of macrophages toward the M1 phenotype may foster control of . Our data show that the deubiquitinating enzyme cylindromatosis () is strongly expressed in macrophages of AD patients and prevents the clearance of . Mechanistically, impaired M1 macrophage polarization by K63-specific deubiquitination of STAT1 and activation of the NF-κB pathway via its interaction with TRAF6, NEMO, and RIPK2. Inhibition of STAT1 and NF-κB, independently, abolished the differences between -infected -deficient and -competent M1 macrophages. Infection of -deficient and wild-type mice with confirmed the protective CYLD function. Collectively, our study shows that impairs the control of in macrophages of AD patients, identifying CYLD as a potential therapeutic target.