The stimulation of inflammasome activation and modulation of proinflammatory cytokine production by house dust mite major allergen in patients with SLE

• Main Authors: Sheng-Jie Yu, 游勝傑
• Other Authors: Jaw-Ji Tsai
• Format: Others
• Language: en_US
• Published: 2015
• Online Access: http://ndltd.ncl.edu.tw/handle/91221554577523767679

博士 === 國立中興大學 === 生物醫學研究所 === 103 === Systemic lupus erythematosus (SLE) is a chronic, remitting and relapsing multisystem autoimmune disease. The major clinical manifestations are rash, arthritis, glomerulonephritis, anemia, and central nerve disorders. Many different autoantibodies which can against autoantigens are found in patients with SLE. Many SLE patients also have allergies. The allergens and immunological events triggering the onset and progression of the clinical manifestations of SLE have yet to be clarified. The most prevalent and well-investigated indoor allergen source is house dust mites (HDM). HDM is highly prevalent in Taiwan, where the climate is subtropical. More than 80% of asthmatic patients are allergic to Dermatophagoides pteronyssinus (Der p) as determined by skin test and specific IgE measurement. HDM major allergen, Der p 2, can induce proinflammatory cytokine production which contributes to airway inflammation and allergic asthma. The correlation between HDM major allergen and SLE and the mechanism of Der p 2 on NLRP3 inflammasome activation remains unclear. Despite improvements in anti-allergy medication, the prevalence of allergic airway inflammation remains high, affecting up to 40% of the population worldwide. Allergen immunotherapy is effective for inducing tolerance but has the adverse effect of severe allergic reaction. In this study, we investigated the immunomodulatory effects of newly discovered cell penetration peptides derived from human eosinophil cationic proteins (CPPecp) and urea-denatured Der p crude extract (DN-Dp) on HDM induced inflammatory responses. The aims of this study are to elucidate the effects of HDM major allergen on B lymphocytes derived from SLE with HDM allergy patients and to investigate the immunomodulatory effect of CPPecp and DN-Dp on inhibition of Der p 2 induced inflammasome activation. A total of three autoantigens, phosphoglycerate kinase 1 (PGK-1), triosephosphate isomerase (TIM) and enolase were identified by autologous serum in B cell lysate derived from HDM allergic SLE patients after group 2 mite major allergen (Der p 2) stimulation. Autoantigen, TRIM-21 expression were also significantly increased in B cells derived from HDM allergic SLE patients. In peripheral blood mononuclear cells (PBMCs) derived from SLE patients, the concentration of anti-PGK-1 was significantly upregulated after Der p 2 stimulation compared to HDM allergic without SLE patients and healthy subjects. Proinflammatory cytokines and chemokines include IL-1beta, IL-6, IL-8, CXCL5 could be upregulated after Der p 2 stimulation in PBMCs derived from HDM allergic SLE patients. Furthermore, we showed that proinflammatory cytokines IL-1β, IL-6 and IL-8 were significantly upregulated in PBMCs derived from HDM allergic patients and SLE patients after Der p 2 stimulation. Expression of NLRP3, ASC, Caspase-1, IL-1β and Caspase-1 activity was upregulated in THP-1 cells after Der p 2 stimulation. Proinflammatory cytokine production, NLRP3 inflammasome activation and caspase-1 activity were downregulated in THP-1 cells and CD14+ cells co-cultured with Der p 2 and CPPecp. The immunomodulatory effect of CPPecp was through upregulation of IFN-α production but not induction of autophagy. In animal model, we demonstrated that the serum level of allergen-specific IgE in mice sensitized with native Der p crude extract after receiving local nasal immunotherapy (LNIT) with DN-Dp was significantly decreased compared to that in the normal saline (NS) treatment group. Expressions of IL-4 were significantly reduced in lung tissues after treatment. Inflammation around the bronchial epithelium improved and airway hypersensitivity was down-regulated. LNIT with DN-Dp can down-regulate IL-1beta, IL-6 and TNF-alpha expression and then decrease Der p-induced allergic airway inflammation. In conclusion, our data demonstrated that long-term allergen exposure could be a contributing factor in the development of SLE and Der p 2 plays an important role in NLRP3 inflammasome activation. CPPecp and DN-Dp have the potential to be novel anti-inflammatory agents for allergen induced inflammation in the future.