Lupus, a chronic autoimmune disease, presents a perplexing clinical spectrum ranging from localized skin manifestations to devastating systemic organ damage. Despite decades of research, the elusive transition from cutaneous lupus erythematosus (CLE) to systemic lupus erythematosus (SLE), and the underlying molecular drivers, have remained poorly understood. Addressing this critical gap, a pioneering research team led by Professor Qianjin Lu at the Chinese Academy of Medical Sciences and Peking Union Medical College Institute of Dermatology has developed an innovative murine model that faithfully recapitulates both cutaneous and systemic phases of lupus. Their work, published on February 3, 2026, in the journal Immunity & Inflammation, heralds a new era in lupus research by implicating keratinocyte-driven inflammation as a primary initiator of autoimmune progression.
Central to this breakthrough is the discovery that peroxisome proliferator-activated receptor gamma (PPARγ), a nuclear receptor and transcription factor known to regulate lipid metabolism and inflammation, is markedly downregulated in the keratinocytes of lupus patients’ skin. This reduction was specifically pronounced in individuals suffering from CLE and SLE, distinguishing lupus-associated skin pathology from other inflammatory dermatoses. Such specificity suggested a targeted molecular lesion confined to skin cells with systemic ramifications, prompting the development of a model that could dissect this relationship in vivo.
Utilizing advanced inducible, keratinocyte-specific gene-editing techniques, the investigators engineered a mouse strain in which the Pparg gene could be selectively ablated in skin cells. By finely tuning the spatial distribution and duration of Pparg knockout, researchers imposed controlled skin inflammation mimicking human CLE. When gene deletion was limited to small skin regions, mice developed localized symptoms such as epidermal thickening, immune infiltration, and erythema, hallmarks of cutaneous lupus. Notably, these mice did not exhibit significant systemic autoimmunity, highlighting the localized impact of keratinocyte dysfunction.
Strikingly, when the extent of Pparg deletion was broadened to larger skin areas, the model manifested progressive autoimmune phenotypes emblematic of systemic lupus. Mice displayed elevated circulating autoantibody titers including anti-dsDNA antibodies, a hallmark of lupus, alongside immune complex deposition within renal glomeruli, manifesting as proteinuria and lupus nephritis. Multiorgan inflammation affecting joints and visceral organs further underscored the systemic nature of the disease triggered by an initial, cutaneous molecular defect. This dose-dependent relationship between skin pathology and systemic autoimmunity is unprecedented, directly linking keratinocytes to lupus pathogenesis beyond a mere target of immune attack.
Beyond faithfully modeling phenotypic transitions, the system demonstrated dynamic disease plasticity seldom captured in previous models. A single gene induction initiated skin and systemic inflammation that, remarkably, spontaneously remitted over time without ongoing intervention, simulating clinical remission phases seen in lupus patients. Moreover, reactivation of Pparg deletion reignited and stabilized systemic disease, offering a controllable platform to examine both relapse and remission, thus mirroring the unpredictable waxing and waning clinical course of human lupus.
The investigators further validated the clinical relevance of their model by exposing mice to ultraviolet (UV) light, a well-known environmental lupus trigger. UV exposure drastically exacerbated cutaneous lesions and accelerated systemic disease transition, epitomizing photosensitivity, a critical lupus phenotype. This environmental susceptibility embedded within the model strengthens its translational applicability for probing how external stimuli interface with genetic predispositions to modulate lupus progression.
Professor Lu and colleagues emphasize that this keratinocyte-centric model transcends traditional paradigms that conceptualize lupus as primarily an immunological aberration originating from lymphocytes or systemic factors. Instead, it positions skin-resident cells as active instigators capable of orchestrating immune system dysregulation and systemic autoimmunity. This represents a conceptual shift, recognizing skin not only as an affected organ but as a driver of disease pathogenesis, opening unexplored avenues for targeted therapeutic interventions aimed at early disease stages.
Equally compelling is the model’s simplicity and practicality. Established on the conventional C57BL/6 mouse background without requiring confounding mutations or chronic chemical sensitization, the model achieves high disease penetrance and reproducibility within a relatively short timeframe. Its responsiveness to dosage and environmental factors renders it an ideal tool for dissecting mechanistic underpinnings of lupus as well as evaluating drug efficacy in preclinical settings. Both systemic immunosuppressants and topical agents yielded quantifiable improvements, underscoring its utility as an experimental platform for screening therapies tailored to disease stage and phenotype.
This research exemplifies integrative science combining human pathology insights with sophisticated genetic engineering to generate an immunocompetent, inducible model recapitulating lupus’s natural history. The ability to visualize and manipulate disease kinetics in real time marks a significant methodological advance, permitting unprecedented exploration of lupus immunopathology from initiation to resolution and relapse.
Looking ahead, the model invites further interrogation of molecular crosstalk between keratinocytes and immune effectors, the identity of soluble mediators driving systemic spread, and the genetic or epigenetic modifiers influencing disease severity. Furthermore, it paves the way for clinical strategies emphasizing early skin-targeted therapies to prevent or mitigate systemic lupus onset, potentially transforming patient outcomes.
In summary, this groundbreaking study by Professor Lu’s team provides a robust experimental framework that not only recreates lupus’s complex clinical spectrum but fundamentally reshapes our understanding of disease origin. By illuminating the skin’s pivotal role in initiating autoimmunity, it opens a transformative chapter in lupus research, promising more precise diagnostics, innovative therapeutics, and ultimately improved prognoses for patients grappling with this multifaceted disease.
Subject of Research: Animals
Article Title: Proinflammatory Keratinocytes Drive a Novel Mouse Model of Autoimmunity with Systemic and Cutaneous Lupus Erythematosus
News Publication Date: 3-Feb-2026
Web References: http://dx.doi.org/10.1007/s44466-025-00024-y
Keywords: Health and medicine, Human health, Diseases and disorders, Health care, Lupus, Autoimmune disorders, Cell biology, Life sciences, Keratinocytes, Skin cells
Tags: autoimmune disease mechanismschronic inflammatory skin conditionscutaneous lupus erythematosus researchdermatology and autoimmune researchinnovative lupus research findingskeratinocytes inflammation rolelupus autoimmune diseasemolecular drivers of lupus transitionmurine model for lupus studiesPPARγ downregulation in lupusskin manifestations of lupussystemic lupus erythematosus progression
