THE IMPACT OF INNATE IMMUNITY AND EPIGENETICS IN THE PATHOGENESIS OF HIDRADENITIS SUPPURATIVA

Olivia M. Burke¹Victoria R. Frerichs¹Dario F. Garcia¹Rivka C. Stone^1,2Hadar Lev-Tov^1,2Tali Czarnowicki¹Robert W. Keane^3,4,5Nkemcho Ojeh^2,6Jelena Marjanovic^1,2Irena Pastar^1,2Marjana Tomic-Canic^1,2Juan Pablo de Rivero Vaccari^3,4,5Andrew P. Sawaya^1,2*

• ¹Dr. Phillip Frost Department of Dermatology and Cutaneous Surgery, Leonard M. Miller School of Medicine, University of Miami, Miami, Florida, United States
• ²Wound Healing and Regenerative Medicine Research Program, Dr. Phillip Frost Department of Dermatology & Cutaneous Surgery, Miami, United States
• ³Department of Physiology and Biophysics, Leonard M. Miller School of Medicine, University of Miami, Miami, Florida, United States
• ⁴The Miami Project to Cure Paralysis, Miami, Florida, United States
• ⁵Department of Neurological Surgery, Leonard M. Miller School of Medicine, University of Miami, Miami, Florida, United States
• ⁶Faculty of Medical Sciences,The University of the West Indies, Cave Hill, Cave Hill, Barbados

Hidradenitis Suppurativa (HS) is a chronic multifactorial inflammatory skin disease with a debilitating impact on quality of life. Here, we review the complex interplay of innate and adaptive immune dysregulation in HS pathogenesis, in the context of microbial dysbiosis, genetic predisposition, cellular dysfunction and epigenetic factors. Hyperactivation of the innate system triggered by follicular occlusion leads to a cascade of activated signaling pathways leading to persistent inflammation as the disease progresses. This immune hyperactivation is further complicated by microbiome dysbiosis, which is associated with dysregulation of inflammasomes and altered expression of host antimicrobial peptides. Keratinocytes, fibroblasts, macrophages, and neutrophils exhibit altered functions, and contribute to the inflammatory cascade and disease chronicity in HS. Epigenetic mechanisms including DNA methylation, histone modifications, and non-coding RNAs modulate immune responses and contribute to aberrant cytokine and chemokine expression that drive the persistent inflammatory state in HS pathogenesis. We highlight the need for future research to explore the concept of epigenetic memory in epidermal stem cells and inflammasome activation to gain a better understanding of these mechanisms and pave the way for development of future novel therapeutic targets and strategies to disrupt the persistent chronic inflammation cycle in this debilitating condition.