Session Type: Abstract Submissions (ACR)
Systemic lupus erythematosus (SLE) presents with a wide spectrum of clinical and immunologic abnormalities. On the other hand, exciting data is emerging about the role of the inflammasome in autoimmune disorders. The assembly of the inflammasome components in innate immune cells (monocytes) results in the rapid activation of Caspase-1, which cleaves pro-IL-1β and pro-IL-18 to generate active forms of these cytokines. Because the precise etiology and the aberrant immune dysfunction in SLE are not completely understood, we hypothesized that: “inflammasome activation occurs in monocytes as a key element on the initiation and amplification of the innate immune response in SLE pathogenesis”. Therefore, the aims of the present study were: 1) To determine whether inflammasome activation occurs in monocytes of SLE patients, and 2) To determine the relationship between inflammasome-related cytokines and disease activity in these patients.
After informed consent, 13 SLE patients and 13 age-matched healthy individuals attending the outpatient arthritis clinic were enrolled. Demographic, laboratory and clinical data were recorded. A score ≥ 6 (SELENA-SLEDAI) was defined as active disease. Purified monocytes were plated and stimulated for 18 h with LPS (100ng/ml) in the presence or absence of Caspase-1 inhibitor. CD14 and Caspase-1 expression was analyzed by flow cytometry. Cell lysates and supernatants were collected for determination of Caspase-1 and NRLP3 protein by Western blot and cytokine levels by ELISA, respectively. Student’s t test and Mann-Whitney tests were used for statistical analysis. The study was approved by the LSU IRB committee.
Ninety two percent (92%) of patients were females and 67% African-Americans. Mean age was 33.2 years and mean disease duration was 10 years. Six patients presented with active disease. Lupus nephritis was diagnosed in 3 patients. The percentage of CD14+/Caspase-1 was significantly higher (p<0.01) in PBMC-monocytes from SLE patients compared to normal controls (70.7 ± 11.1 vs 33.5 ± 13.0, respectively). These findings directly correlated with higher plasma levels of IL-1β (0.4 ± 0.28 vs 0.15 ± 0.24 pg/ml, p<0.05) and IL-18 (725.2 ± 215.4 vs 479.2 ± 125.2 pg/ml, 0.01). Caspase-1 expression was confirmed by Western blot. Purified monocytes from SLE patients displayed a robust inflammatory response after LPS stimulation where Caspase-1, NLRP3, IL-1β and IL-18 were highly expressed. The production of IL-18 was reduced by 3 fold when Caspase-1 inhibitor was added to the cultures. Plasma levels of IL-18 were significantly higher in SLE clinical patients with active disease (p<0.05). Neither Caspase-1 or IL-1β expression was associated with SLE clinical features and disease activity.
Innate immune cells in SLE patients exhibited enhanced inflammasome activation, characterized by high expression of Caspase-1, NLRP3, IL-1β and IL-18, and in-vitro suppression of IL-18 production by Caspase-1 inhibitor. These findings provide novel insights into the pathogenesis of SLE and potential new avenues to explore the development of newer therapeutic strategies in the management of the disease.
R. Perez Alamino,
Genentech and Biogen IDEC Inc.,
L. R. Espinoza,
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/role-of-inflammasome-activation-in-systemic-lupus-erthematosus-are-innate-immune-cells-activated/