Dysregulation in keratinocytes drives systemic lupus erythematosus onset.

Abstract

Systemic lupus erythematosus (SLE) is a complex, multiorgan autoimmune disorder. Although it is widely believed that SLE originates from immune cell dysregulation, the etiology of SLE is not yet clear. Here, we propose a new theory in which SLE can be directly initiated by molecular alterations in keratinocytes rather than immune cells. We found that the level of peroxisome proliferator-activated receptor gamma (PPARγ) is substantially reduced in the skin lesions of patients, and replicating this reduction in mice led to rapid disease onset with multiple hallmarks of SLE. As PPARγ decreases in keratinocytes, which is accompanied by increased occupancy of interferon regulatory factor 3 at the type I interferon locus, dendritic cells (DCs) are recruited to the epidermis and are activated by keratinocyte-secreted type I interferon. These activated DCs migrate to local draining lymph nodes, where they activate CD4⁺ T cells in a non-MHC II-dependent manner, promoting their differentiation into effector T cells and thus contributing to disease onset. Our study revealed that the dysregulation of keratinocytes can be a pathogenic driver of SLE and describes a new mouse model that mimics human SLE. Our data also emphasize the pivotal role of skin immunity in the onset of systemic autoimmune disease.