Introduction
Cutaneous lupus erythematosus (CLE) represents a multifactorial autoimmune skin disorder in which genetic predisposition, environmental triggers, and immunological disturbances converge to initiate and sustain chronic inflammation. Ultraviolet radiation, smoking, and certain medications are capable of inducing keratinocyte apoptosis, resulting in the release of nucleic acids that activate innate immune sensors. This activation promotes the production of type I and type III interferons, fueling a feed-forward inflammatory cycle. Emerging evidence suggests that several skin-resident and infiltrating immune cells—including keratinocytes, dendritic cells, T cells, B cells, neutrophils, and macrophages—play essential roles in modulating disease severity. Understanding these cellular interactions is central to developing precise molecular interventions.
Emerging Insights Into Keratinocyte-Driven Interferon Signaling
Recent studies highlight keratinocytes as primary contributors to the interferon-rich microenvironment that precedes visible CLE lesions. Upon exposure to UV radiation or other environmental stressors, keratinocytes undergo apoptosis and release nucleic acids that activate pattern-recognition receptors. This activity enhances the production of type I IFNs, challenging the classical paradigm that plasmacytoid dendritic cells are the principal interferon producers. The keratinocyte-driven IFN response attracts and activates multiple inflammatory cell subsets, indicating that therapeutic strategies targeting keratinocyte signaling could modify early disease progression and reduce flares.
Dendritic Cell and Myeloid Cell Dysregulation in the CLE Microenvironment
Dendritic cells, including inflammatory myeloid subsets, are increasingly recognized for their pivotal roles in amplifying cutaneous inflammation. Although plasmacytoid dendritic cells display functional impairment in CLE, other myeloid cells compensate by producing cytokines, presenting autoantigens, and promoting T-cell activation. This dysregulated myeloid activity creates a sustained inflammatory niche that perpetuates tissue damage. Characterizing the transcriptomic and functional profiles of these myeloid populations is essential for developing targeted inhibitors capable of interrupting disease amplification at its source.
T-Cell-Mediated Tissue Damage and Immune Propagation
Cytotoxic CD8⁺ T cells infiltrate CLE skin and directly contribute to basal keratinocyte destruction. Meanwhile, CD4⁺ T cells secrete pro-inflammatory cytokines that enhance dendritic cell activation, B-cell differentiation, and interferon production. This coordinated T-cell response not only drives lesion formation but also maintains chronicity by reinforcing innate immune activation. Current research is exploring surface receptors, cytokine signatures, and T-cell clonality patterns that may serve as biomarkers or therapeutic targets for modulating T-cell-driven pathology.
Autoantibody Production, Immune Complex Formation, and B-Cell Activation
B cells and plasma cells play central roles in CLE by generating autoantibodies that recognize nuclear antigens released during keratinocyte apoptosis. These autoantibodies combine with antigens to form immune complexes, which deposit in the skin and trigger pro-inflammatory cascades via complement activation and Fc-receptor engagement. Persistent autoantibody production contributes to lesion chronicity and systemic immune activation. Ongoing research focuses on delineating the mechanisms that support B-cell survival in inflamed skin and evaluating novel therapeutics that disrupt antigen presentation or B-cell signaling pathways.
Neutrophil and Macrophage Contributions to Chronic Inflammation
Neutrophils exacerbate CLE through the release of neutrophil extracellular traps (NETs), exposing autoantigens and activating interferon pathways. Macrophages, although essential for tissue homeostasis, become dysfunctional in CLE by failing to clear apoptotic cells and immune complexes efficiently. They further intensify inflammation through excessive cytokine secretion and antigen presentation. Understanding how these innate immune cells interact with keratinocyte-derived signals and adaptive immune responses may reveal new therapeutic angles aimed at restoring immune resolution and reducing tissue damage.
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