Adherens Junction dysfunction in Hidradenitis Suppurativa

Project Summary Hidradenitis Suppurativa (HS) is a chronic, debilitating inflammatory skin disease that affects the pilosebaceous units in skin folds in 1-4% of the population. It often leads to disfiguring and permanent scarring. Histologically, lesions exhibit epidermal hyperplasia, hair follicle abnormalities, and inflammation. HS is aggravated by mechanical stress1-3. Treatment often involves a combination of surgical and medical management. Adalimumab, the only FDA-approved therapy, is effective in 20-30% of patients. Gaps in our understanding of the mechanisms involved in HS preclude the development of more effective and targeted therapies for this debilitating, under-recognized and often misdiagnosed disease. We discovered that the expression of E-cadherin (E-cad) and p120 catenin (p120), two critical proteins for keratinocyte adherens junction (AJ) structure and function, is lost in 19 of 23 samples from severe HS lesions. Even in non-lesional skin from HS patients, we observe a complete loss or translocation of E-cad or p120 to the cytoplasm. Moreover, the degree of E-cad or p120 protein loss correlates positively with disease severity. A role for AJ protein loss in HS is further substantiated by the observation that mice lacking E-cad or p120 in their skin exhibit HS-like histological features. A key question is whether E-cad and p120 loss contributes to the disease process through destabilizing keratinocyte cell junctions or whether it results from the inflammatory process: we posit that it is both. Here, we will rigorously investigate keratinocytes, not just as innocent bystanders, but as active contributors to HS pathogenesis. Our data suggest that HS keratinocyte adhesion is at the center of a pathomechanism characterized by a feed forward cycle in which loss of adhesion drives inflammatory cytokine expression. Expression of these cytokines further weaken adhesion, which, in turn, drives further expression of cytokines, leading to loss of homeostasis and more inflammation. Therefore, we propose to delve into this pathogenic cycle with two synergistic aims using in vitro culture models, murine models, and samples from human subjects, including keratinocytes, blood, and suction blister fluid from both normal subjects and HS patients. In Aim 1, we will determine how the loss of E-cad and p120 in HS keratinocytes contributes to HS pathophysiology. In Aim 2, we will determine how inflammatory mediators of HS induce loss of E-cad, p120 and adhesion in keratinocytes. We will correlate our results with subject demographics and clinical information to determine any associations with biological variables. Successful completion of this project will elucidate the mechanism by which keratinocytes contribute to the pathogenic cycle of inflammation and tissue disruption in HS. This new knowledge is critical to our overall understanding of HS pathophysiology. Future therapeutic approaches will result from our efforts to discover new HS pathomechanisms in support of NIAMS goals to improve the treatment for this debilitating disease.