Keratinocytes: pleiotropic orchestrators of cutaneous immunity and Inflammation - Emerging therapeutic paradigms in...

Keratinocytes, the principal cellular constituents of the epidermis, have transcended their conventional barrier function to emerge as master regulators of cutaneous immune homeostasis and inflammatory pathogenesis. In inflammatory skin diseases such as psoriasis, atopic dermatitis, and systemic lupus erythematosus, keratinocytes orchestrate complex inflammatory cascades through intricate signaling networks.

We conducted a comprehensive literature search in the PubMed database. The search was performed using the following key terms: "Keratinocytes", "Inflammation", "Skin immune diseases", "Immune cell", "Glucocorticoids", "Inflammasomes", "Antioxidants", "Neuropeptide" and "Single-Cell Technologies".

In this review, we summarize that keratinocytes play a pivotal role in inflammatory skin pathologies by engaging in bidirectional communication with T lymphocyte subsets, establishing self-amplifying cytokine circuits (e.g., the HMGB1-mediated loop in SLE and the IL-23/Th17 axis in psoriasis), and constitutively producing local glucocorticoid metabolites. Their immunoregulatory capacity is executed through pattern recognition receptor activation and the maintenance of redox balance via antioxidant defense systems such as the SOD2/Nrf2/ARE pathway. Keratinocytes can produce and secrete inflammasomes and neuropeptides, thereby participating in the regulation of inflammation, pruritus, pain and neuro‑immune crosstalk. Furthermore, cutting-edge single-cell transcriptomic profiling has revealed unprecedented keratinocyte heterogeneity and disease-specific subpopulations. In summary, keratinocyte-targeted strategies offer promising interventions to break pathogenic cycles and restore epidermal barrier function.