Keratinocytes, the primary cells of the epidermis, play a crucial role in the pathogenesis of CLE. In genetically susceptible individuals, exposure to UV radiation and other environmental factors induces keratinocyte death, leading to the release of damage-associated molecular patterns (DAMPs), including endogenous nucleic acids, high-mobility group box 1 (HMGB1) protein, and autoantigens such as Ro52 [70, 71]. DAMPs are recognized by pattern recognition receptors (PRRs), such as melanoma differentiation-associated protein 5 (MDA5), on keratinocytes, triggering the transcription of IFN-regulated genes via a TLR-independent pathway [10, 72]. This inflammatory response amplifies the autoimmune cascade in CLE [72]. Additionally, HMGB1 functions as a proinflammatory cytokine and an autoantigen, further contributing to tissue damage in CLE [73].

Additionally, keratinocytes secrete IFN-κ and IFN-λ (type I and type III IFNs), which, via self-signaling mechanisms, amplify the expression of IFN-responsive proinflammatory cytokines, such as IL-6, and chemokines, such as CXCL9-11, which bind to C-X-C motif chemokine receptor 3 (CXCR3) ligands to recruit more immune cells [72, 74, 75]. Consequently, cytotoxic T cells induce additional keratinocyte death through CXCR3-mediated mechanisms [70, 71]. This ongoing damage activates antigen-presenting cells (APCs), particularly DCs, which stimulate T- and B-cell responses. The autoAbs produced as a result of this process further target keratinocytes, perpetuating tissue damage and inflammation in CLE.

IFNs are activated via Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling [74]. Nucleic acid motifs also activate the inflammasome via absent in melanoma 2 (AIM2) [76]. Interestingly, IFN-κ expression is upregulated, and basal phospho-STAT (pSTAT) activity is greater in the healthy-appearing skin of CLE patients than in the skin of patients with other chronic inflammatory skin diseases, such as psoriasis [74].

UVB radiation upregulates the expression of Ro52 in keratinocytes and promotes its interactions with TNF-like weak inducer of apoptosis (TWEAK), which binds to its receptor, fibroblast growth factor-inducible 14 (Fn14) [77, 78]. This interaction activates the NF-κB and PI3K/Akt pathways, leading to increased expression of Ro52 and activation of proinflammatory pathways, resulting in increased levels of proinflammatory cytokines [77, 78]. This sequential chemokine production sustains inflammation in the epidermal layer [62]. In established CLE lesions, keratinocyte apoptosis and proinflammatory chemokine production are limited to the dermal-epidermal junction, resulting in interface dermatitis [79]. On the other hand, keratinocytes from the healthy-appearing skin of CLE patients are more sensitive to UV radiation-induced cytotoxicity than keratinocytes from healthy donors are [80, 81].

UV radiation also alters keratinocyte DNA, generating immunostimulatory motifs such as 8-hydroxyguanosine [72]. Interestingly, compared with healthy individuals, CLE and SLE patients exhibit a larger number of dying keratinocytes and impaired clearance [81]. In CLE, autoAbs further amplify this response [82]. However, autoAbs targeting ribonucleoproteins may directly drive the formation of lupus lesions in mice [83].

pDCs and DCs are APCs that play important roles in regulating inflammation in CLE and contribute to lesions. pDCs are specialized type I IFN-producing cells that express TLR7 and TLR9 and thus recognize nucleic acids, especially in the form of ICs [63]. pDCs are observed in skin biopsy samples from CLE patients, both with and without lesions, and are involved in the pathogenesis of both SLE and CLE [84–86]. The majority of pDCs are located within perivascular inflammatory areas in the dermis, whereas others are situated along the dermal-epithelial junction [85]. However, not all skin lesions contain pDCs [87]. Recently, single-cell RNA and spatial RNA sequencing revealed that the skin of CLE patients, both with and without lesions, harbors a type I IFN-rich environment attributed to CD16⁺ DCs, leading to proinflammatory subtypes [88].

Both DCs and pDCs are recruited to skin lesions through CXCL-chemokine interactions with CXCR3 by sensing nucleic acids released following keratinocyte death [62]. pDCs are further stimulated via TLRs, particularly TLR7 and TLR9 [89]. TLR9 and CD32 are activated upon the uptake of nucleic acids and ICs via endocytosis [90]. Once activated, pDCs produce large amounts of type I and type III IFNs, cytokines, and interleukins (ILs), further perpetuating the autoimmune response [91]. Additionally, the presence of type I IFN is essential for pDC maturation and migration [92]. Moreover, pDCs secrete large amounts of TNF and IL-6 in response to IFN-α, which further increases apoptosis [93], and contribute to the regulation and recruitment of T, B, and natural killer (NK) cells. The number of peripheral circulating pDCs is reduced in patients with LE, as pDCs preferentially migrate to affected tissues, including the skin [63]. While pDCs are most abundant in active lesions, low-level infiltration in non-lesional skin is a key subclinical feature that distinguishes the skin of CLE patients from that of healthy controls and may prime the skin for future flares [88, 94–96], with infiltration noted after skin injury [63] or UV exposure [97]. In a lupus-prone murine model, transient depletion of pDCs before disease initiation was found to ameliorate autoimmunity [86]. In human studies, anti-BDCA2 monoclonal antibodies, which specifically target the BDCA2 receptor on pDCs, have been shown to suppress type I IFN production and inflammatory mediators, thereby alleviating lupus-associated cutaneous manifestations [98, 99].

NK cells are abundant and proliferate in CLE skin lesions, and the number of these cells in the peripheral blood decreases due to their trafficking from blood to tissue [100–103]. In SLE, peripheral blood NK cell counts are inversely correlated with disease activity [104]. Compared with those of healthy controls, the NK cells of lupus patients secrete more IFN, and their cytotoxic functions are impaired [101, 105]. However, the precise role of NK cells in CLE pathophysiology is unclear, although it is known that NK cells colocalize with CD8⁺ T cells at the dermal-epidermal junction, releasing granzyme B to induce keratinocyte apoptosis [100]. Type I IFNs provide negative feedback, reducing the amount of granzyme B released and limiting tissue damage. Invariant NK cells secrete IFN-γ, influencing both inflammatory and anti-inflammatory responses to tissue damage [100].

Neutrophils, as early responders in the innate immune system, are present in the skin before lesion onset in murine models of CLE [106]. UV radiation and other stimuli induce keratinocyte death, inducing the release of DAMPs that activate neutrophils. These neutrophils secrete antimicrobial peptides (AMPs), such as LL-37, and reactive oxygen species (ROS) and form neutrophil extracellular traps (NETs) composed of chromatin, histones, and other intracellular contents [107, 108]. Elevated levels of LL-37 and other AMPs have been observed in CLE lesions compared with healthy skin [109, 110]. The increases in NETosis and IL-17 externalization by neutrophils in SLE-affected skin suggest that NETs and IL-17 play a role in tissue damage and that the number of NETs and IL-17 levels are correlated with disease activity [104, 106]. In patients with various CLE subtypes, including tumid lupus, panniculitis, ACLE, and DLE, NETs are present in lesions, with higher NET numbers in tumid lupus, ACLE, and DLE lesions than in SCLE lesions, indicating distinct roles for neutrophils depending on the disease subtype [111, 112]. NETs also impact pDCs by complexing with double-stranded DNA (dsDNA) and LL-37, which are internalized through TLR9 and subsequently produce type I IFN in SLE [113, 114]. Additionally, LL-37/dsDNA complexes can function as autoantigens [115]. Notably, UV light exposure leads to the recruitment of neutrophils to the skin, which may further lead to temporary damage and upregulation of type I IFN gene expression in other organs, such as the kidneys [112]. However, the precise pathophysiological role of neutrophils and AMPs in CLE remains to be elucidated.

Furthermore, monocytes act as APCs and are recruited and activated by colony-stimulating factor 1 (CSF-1) produced by keratinocytes upon UV exposure, leading to increased keratinocyte apoptosis [116]. Moreover, monocyte-derived DCs, the numbers of which are elevated in both the lesional and healthy skin of SLE patients, may contribute to CLE pathology because of their strong activation signature [88].

Macrophages act as APCs and play roles in processes such as phagocytosis and cytokine production [117]. An increased number of macrophages in CLE lesions predicts a poor response to hydroxychloroquine [118, 119]. CD68-positive macrophages expressing FasL are found around hair follicles and contribute to hair follicle destruction through Fas-FasL interactions in CLE [120]. UVB irradiation increases the expression of CSF-1 in keratinocytes, thereby attracting macrophages that trigger keratinocyte apoptosis in lupus-prone mice with CLE but not in lupus-resistant mice with CLE [116]. Interestingly, macrophage infiltration after UV exposure may cause systemic symptoms such as arthralgia, weakness, fatigue, and headache [118].

T cells, including CD4⁺, CD8⁺, memory, and γδ T cells, regulatory T (Treg) cells, and T helper 17 (Th17) cells, play crucial roles in the pathogenesis of CLE [79]. CD4⁺ T follicular helper and T peripheral helper cells promote B-cell activation and autoAb production [121–124]. The role of Treg cells in CLE remains unclear, as studies have reported both increased and decreased numbers of these cells in SLE skin samples [125–128]. In lupus-prone mice, UV exposure enhances CD4⁺ and CD8⁺ T-cell activation in draining lymph nodes while suppressing Treg cells, an effect that is amplified in a type I IFN-dependent manner [129]. However, whether this mechanism occurs in the skin and its impact on CLE inflammation remains unknown. Th1 cells are considered key drivers of CLE pathogenesis, with a notable shift toward Th1-associated chemokines across all CLE subtypes [130, 131]. Th17 cells, which are prevalent in individuals with IL-2-deficient SLE, exacerbate inflammation by skewing naive T-cell differentiation toward Th17 cells rather than Treg cells [132, 133].

Upon UV exposure, keratinocytes release chemokines such as CXCL9, CXCL10, and CXCL11, which bind to the CXCR3 receptor on T cells. This interaction results in the recruitment of autoreactive cytotoxic T cells, triggering keratinocyte death [70–72, 74, 75]. Among these chemokines, CXCL10 plays a key role in directing CXCR3-expressing T cells to skin lesions. Consequently, T-cell activation occurs through interactions between the T-cell receptor (TCR) and major histocompatibility complex (MHC) class II, initiating downstream signaling [134]. This cascade involves increased phosphorylation of signaling molecules and increased calcium influx, which is mediated by the association of spleen tyrosine kinase (SYK) with the Fc receptor γ-chain (FcRγ), further amplifying TCR signaling [135].

Upon recruitment, cytotoxic CD8⁺ T cells target basal keratinocytes, contributing to interface dermatitis, as observed via H&E staining [136]. These cells express granzyme B, which is elevated in CDLE scarring lesions compared with SCLE lesions, suggesting a role for the cells in scarring pathophysiology [137]. While Th2 cells may initiate inflammation, Th1 cells dominate established lesions, promoting type I IFN production by cytotoxic T cells and macrophages [136, 138]. Transcriptomic analysis of skin T cells revealed an IFN-rich signature, with reduced numbers of cytotoxic and effector T cells compared with those in lupus nephritis biopsy samples [139]. T cells induce keratinocyte apoptosis via FAS/FASL interactions [120], whereas IL-21 from Th cells increases granzyme B levels in pDCs and NK cell-mediated keratinocyte damage [140, 141]. However, type I IFNs suppress granzyme B production in pDCs [140]. Moreover, Th cells respond to nucleosomes, driving anti-DNA antibody production in B cells in SLE [142–144]; Th clones produce IL-2, IFN-γ, and IL-4; and lupus CD4⁺ T cells overexpress perforin through epigenetic regulation via DNA methylation [68, 145].

Interestingly, CLE patients present significantly lower numbers of CD4⁺, CD8⁺, Tregs, and γδ-T cells than individuals with other inflammatory skin diseases and healthy controls do, contributing to autoimmunity via impaired immunosuppressive function [125, 134, 146]. The proportions of CD4⁺ T cells and FOXP3⁺ T cells and the CD4/CD8 ratio are significantly lower in SCLE lesions than in CDLE lesions [126]. Additionally, a proteomic study revealed a unique increase in IL-16 expression in CLE lesions [147].

When upregulated, CD40L on T cells interacts with B cells to promote maturation and antibody secretion [134] and engages APCs to amplify the TCR signal [148]. Signaling pathways, such as the cyclic adenosine monophosphate (cAMP)-dependent phosphorylation and protein kinase C (PKC) pathways, are either inhibited or activated, similar to the PI3K pathway [134].

B cells play a pivotal role in the pathogenesis of CLE through multiple mechanisms, primarily via autoAb production and interactions with T cells [149–152]. Following keratinocyte death induced by UV exposure or other triggers, naive B cells become activated, differentiate into plasma cells, and begin secreting autoAbs, a process further amplified by IFN signaling [153, 154].

Plasma cell differentiation, survival, and sustained autoAb production are supported by survival signals mediated through B-cell-activating factor, also known as B-lymphocyte stimulator (BAFF/BLyS) and IL-6 from surrounding cells [149, 155]. Additionally, Th cells support plasma cell differentiation [156], as somatic hypermutation and isotype switching depend on CD40 and IL-21 [149]. IL-21 and TLR7/9 facilitate B-cell recruitment to inflammation sites in CLE lesions and localized autoAb production in mouse models [157], whereas IL-17 recruits immune cells and increases B-cell autoAb production in SLE [133]. Plasma cells can accumulate at the site of inflammation [158], whereas B cells form clusters in the skin and arrange in lymphoid-like structures, called tertiary lymphoid organs/structures (TLOs) [87, 159].

B cells interact with keratinocytes via BAFF and its receptor (BAFF-r) in both SLE and CLE; BAFF is expressed by lesional keratinocytes, and associated receptors [BAFF-r, transmembrane activator and CAML (calcium-modulating cyclophilin ligand interactor) interactor (TACI), and B-cell maturation antigen (BCMA)] are expressed by B cells [87, 160–162]. BAFF is essential for B-cell maturation [163], and its expression in keratinocytes can be induced by immunostimulatory DNA motifs, highlighting its importance in CLE [161].

Patients with ACLE and SCLE commonly have detectable circulating autoAbs, including anti-Ro (Ro60/Ro52), anti-La, and anti-galectin-3, which are rarely present at measurable levels in CDLE [104, 164, 165]. These autoAbs are associated with HLA-DR3 in SLE [165] and with disease severity [166]. AutoAbs form ICs at the dermal-epidermal junction, resulting in the characteristic “lupus band” visible via IF, which aids in CLE diagnosis [167–169]. In SLE, B-cell deposition in nonlesional skin is correlated with a worse prognosis [170], and the extent of B-cell infiltration in lesional skin varies by LE subtype [87, 171], with DLE patients showing a stronger B-cell signature and greater enrichment of B cells than ACLE and SCLE patients [172]. Compared with similar SLE lesions, isolated CLE lesions exhibit a more pronounced B-cell signature, linking cutaneous and systemic disease activity [171]. Despite these differences, circulating B-cell populations largely overlap between SLE and isolated CLE.

Circulating anti-Ro and anti-La autoAbs are strongly associated with photosensitivity, with Ro proteins detected in CLE lesions [170, 173–176]. These findings are supported by the observation that UV exposure induces keratinocyte apoptosis and promotes Ro antigen translocation to the cell surface, where anti-Ro autoAbs can bind [177–181]. Additionally, UVB upregulates Ro/SSA and La/SSB expression on apoptotic keratinocytes, enhancing autoAb interactions [178, 179]. These findings highlight the role of autoantigen redistribution in the aberrant UV response observed in lupus.

The presence of anti-Ro autoAbs in the serum correlates with increased IL-17A⁺ lymphocytes in lesional skin in SCLE, and Ro52 deletion in mice triggers Th17-driven inflammation [182, 183]. Ro52 negatively regulates IFN production, reducing inflammatory cytokine levels, while its deficiency leads to the development of CLE-like lesions [182, 184–186]. Moreover, Ro60, an RNA-binding protein, may mediate UV responses, and Ro60 deficiency in mice results in lupus-like features, including autoAb production, glomerulonephritis, and photosensitivity [187–189]. Nonetheless, the functional link between Ro52/Ro60 autoAbs and their targets remains unclear.

B cells drive skin damage in addition to autoAb production through IFN-dependent processes, including antigen presentation, receptor engagement, and cytokine signaling [153]. Additionally, IL-6 production by B cells sustains the survival of these cells [149, 190]. Notably, B-cell signatures and infiltrates in autoAb-negative CLE highlight the role of B cells in fueling autoimmune reactions through antigen presentation and T-cell activation [87, 172].

Overall, cutaneous lupus exemplifies how environmental triggers, such as UV light, initiate a cascade of immune crosstalk between innate and adaptive immune cells that drives chronic skin inflammation in cutaneous SLE. Keratinocyte injury leads to the release of cytokines, chemokines, and nucleic acids that activate pDCs, which subsequently secrete type I IFNs to orchestrate T- and B-cell activation. CD4⁺ and CD8⁺ T cells amplify local inflammation through IFN-γ secretion and cytotoxic activity, while B cells produce autoAbs that form ICs, further engaging innate immune pathways. This tightly orchestrated network of keratinocytes, pDCs, and adaptive immune cells sustains a self-perpetuating inflammatory loop that underlies the chronicity of cutaneous SLE.