Activation of death receptor 3 signaling pathway prevents antibody-mediated transfusion-related acute lung injury via αDR3 antibody / 中国输血杂志

ABSTRACT

【Objective】 To explore the efficacy and possible mechanisms of activation of Death receptor 3 (DR3) signaling pathway in the prevention of antibody-mediated transfusion-related acute lung injury (TRALI) via DR3 agonistic (αDR3) antibody. 【Methods】 8-10-week-old male wild-type Balb/c mice (40) were randomly divided into Naïve group, isotype control group, TRALI model group, and intervention group. Mice without any treatment served as Naïve group. Isotype and TRALI model were established by intraperitoneally priming 8-10-week Balb/c mice with LPS 18 h prior to injection of an IgG2a isotype antibody and anti-MHC-Ⅰ antibody via tail vein, respectively. Intervention group mice were intraperitoneally injected with a single dose of αDR3 antibody (1 mg/kg) on day 1; after 3 days, the mice were challenged with LPS 18 h prior to injection of an anti-MHC-I antibody. The lung tissues and spleens of mice in each group were collected at the mice died or 2 hours after TRALI modeling for the lung injury severity. Spleens were collected to measure the proportion of Treg by flow cytometry. Foxp3, iNOS, and CD206 immunohistochemical staining combining with optical density analysis of lung tissues were used to represent Treg, M1 macrophages and M2 macrophages, respectively. The concentration of IL-6, IL-1β, TNF-α, and IL-10 cytokines in lung tissues was detected via Cytometric Beads Array. 【Results】 Compared with TRALI group, 1) the lung injury of mice were significantly alleviated in intervention group; 2) the proportion of Treg(%) in the spleens (9.295±1.349 vs 2.257±0.610, P<0.05), Foxp3 expression of Treg in the lungs (0.302 6±0.052 6 vs 0.230 2±0.016 3, P<0.05), and the concentration of Treg derived cytokines IL-10 in the lungs (29.52±8.885 vs 8.045±1.911, P<0.05) increased significantly in intervention group; 3) the iNOS expression of M1 macrophages (0.209 6±0.013 9 vs 0.279 6±0.045 2) and the concentration of M1 macrophage derived cytokines IL-6 (23.22±19.35 vs 301.1±157.7), IL-1β (46.76±25.34 vs 307.6±183.8), and TNF-α (45.99±14.16 vs 143.9±44.43) in the lungs was significantly reduced(P<0.05), while CD206 expression of M2 macrophages (0.291 2±0.032 1 vs 0.221 5±0.012 7) and the concentration of M2 macrophage derived IL-10 cytokines (29.52±8.885 vs 8.045±1.911) in the lungs increased significantly in intervention group(P<0.05). 【Conclusion】 Activation of DR3 signaling pathway by αDR3 antibody prevents antibody-mediated TRALI via expanding Treg, which regulates macrophage polarization by IL-10 derived from Treg.