Keratinocytes: A key player in skin immunity and their emerging roles in secondary lymphedema

Keratinocytes, once viewed as inert epidermal scaffolds, are now recognized as active participants in the cutaneous immunity. They orchestrate local immune responses by releasing cytokines, chemokines, and alarmins that shape innate and adaptive inflammation. Dysregulated keratinocyte-immune interactions underline chronic inflammatory skin disorders, such as atopic dermatitis, psoriasis, and cutaneous lupus erythematosus. More recently, keratinocytes have been identified as key contributors to secondary lymphedema, a chronic inflammatory and fibrotic condition historically attributed to lymphatic dysfunction. This review revises our understanding of keratinocytes as immunomodulatory cells, while focusing primarily on their emerging role in the pathogenesis of secondary lymphedema. We highlight and appraise recent evidence that lymphatic stasis reprograms keratinocyte differentiation, induces type 2 helper T cells-skewed inflammatory responses, and perpetuates chronic inflammation and fibrosis. Understanding this keratinocyte-immune-lymphatic axis may unveil novel therapeutic targets beyond traditional lymphangiogenic approaches.