The transcription regulators ZNF750 and LSD1/KDM1A dampen inflammation on the skin's surface by silencing pattern recognition receptors.

The surface of the skin is continually exposed to pro-inflammatory stimuli; however, it is unclear why it is not constantly inflamed due to this exposure. Here, we showed undifferentiated keratinocytes residing in the deep epidermis could trigger a strong inflammatory response due to their high expression of pattern recognition receptors (PRRs) that detect damage or pathogens. As keratinocytes differentiated, they migrated outward toward the surface of the skin and decreased their PRR expression, which led to dampened immune responses. ZNF750, a transcription factor expressed only in differentiated keratinocytes, recruited the histone demethylase KDM1A/LSD1 to silence genes coding for PRRs (TLR3 , IFIH1 /MDA5, and DDX58 /RIG1). Loss of ZNF750 or KDM1A in human keratinocytes or mice resulted in sustained and excessive inflammation resembling psoriatic skin, which could be restored to homeostatic conditions upon silencing of TLR3. Our findings explain how the skin's surface prevents excessive inflammation through ZNF750- and KDM1A-mediated suppression of PRRs. [Display omitted] • Differentiated keratinocytes dampen inflammation due to silencing of PRR expression • ZNF750 recruits KDM1A to silence PRR expression in differentiated keratinocytes • Zfp750 −/− and Kdm1a −/− mice show increased and sustained skin inflammation from damage • Tlr3 deletion alleviates the hyperinflammatory response in Zfp750 −/− and Kdm1a −/− mice It is unclear why the surface of the skin, which constantly encounters pro-inflammatory stimuli, is not always inflamed. Liu et al. show that as differentiated keratinocytes migrate toward the surface of the skin, they turn off the expression of pattern recognition receptors through the activities of ZNF750 and KDM1A. [ABSTRACT FROM AUTHOR]