Background Recently, IL-1 is implicated in the pathogenesis of autoinflammatory syndromes, which characterized by rash, fever, systemic polyarthritis and neurological comorbidity. Recently, IL-1 is being accepted as a therapeutic target of adult onset still's disease, systemic-onset juvenile idiopathic arthritis, pseudogout, and macrophage activation syndrome. However, to date, animal model of adult onset “IL-1 disease” has not been reported. Herein, we newly established IL-1alpha transgenic mice with conditional regulation of IL-1alpha overexpression, which mimicked adult onset IL-1 disease in humans.
Objectives The objective of the present study is to clarify the pathology of adult onset IL-1 disease through these mice.
Methods Human IL-1alpha (hIL1alpha) conditional transgenic (cTg) mice were generated as loxP-neomysin resistant gene (Neo)-polyA-loxP-hIL1alpha sequence under an beta-actin promotor in a C57BL/6 background. In non-inducing condition, Neo was expressed without hIL1alpha-expression, whereas in inducing condition in the presence of Cre, Neo-polyA sequence was popped out, and hIL1alpha overexpression was induced. We crossed inducible MxCreTg mice with hIL1alphacTg to yield MxCre/hIL1alphacTg. PolyIpolyC (pI-pC) was administered to 8 week-old cTg mice to activate Mx promoter. The mice were sacrificed two weeks after pI-pC administration, and the severity of arthritis was evaluated using arthritis score, followed by a histological examination.
Results One week after pI-pC administration, hIL1alphacTg mice exhibited inflammatory arthritis in knee and hip joints at 1-week post-administration and in elbow and shoulder joints at 2-week post-administration. The incidence of the arthritis was 100%. Another phenotypes of the Tg mice was loss of body weight and dermatitis. Histopathologically, loss of cartilage, bony erosion, neutrophil infiltration, and the formation of pannus-like tissues were observed in all the Tg mice. The number of white blood cells and platelets was significantly elevated, in contrast, red blood cell count and hemoglobin level were decreased due to chronic inflammation. Serum levels of IL-6 and leukemia inhibitory factor (LIF) as well as transgene-derived IL1alpha were significantly elevated. The bone mineral density of the femur was significantly reduced. Flow cytometric analysis revealed that the proportion of Mac1+Gr1+ cells were significantly elevated in joint fluid and bone marrow, instead, the proportion of CD3+ and B220+ cells were significantly decreased in bone marrow.
Conclusions We generated a mouse model of autoinflammatory syndromes in which systemic inflammatory arthritis was intentionally controlled by pI-pC administration. The incidence of large joint arthritis was 100% even in a relatively arthritis-resistant C57BL/6 background. Conditional overexpression of IL-1alpha in mice offers a useful tool to establish a new therapeutic strategy for IL-1 disease.
Disclosure of Interest : None declared