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Milk fat globule-EGF factor 8 suppresses the aberrant immune response of systemic lupus erythematosus-derived neutrophils and associated tissue damage.

ABSTRACT: Abnormal features of the systemic lupus erythematosus (SLE)-derived neutrophils, promoted aberrant immune response, have inspired new studies of the induction of autoimmunity and the development of organ damage in SLE. In this study, we explore the effect of milk fat globule-EGF factor 8 (MFG-E8) on the aberrant nitrification features in pristane-induced lupus. SLE patients and mice with pristane-induced lupus develop autoantibodies associated with MFG-E8 overproduction. However, the deletion of MFG-E8 leads to uncontrolled early pulmonary and peritoneal inflammation and tissue damage in mice with pristane-induced lupus. Consistent with these findings, MFG-E8-deficient mice that are exposed to pristane show enhanced neutrophil accumulation and increased neutrophil death, including apoptosis, necrosis and NETosis, as well as impaired phagocytosis of macrophages. The consequences are the expansion of diffuse pulmonary hemorrhage, increased anti-nuclear antibody, anti-dsDNA antibody and anti-neutrophil cytoplasmic antibody levels, and enhanced immune complexes deposition and neutrophil extracellular traps (NETs) formation in the lung and kidney tissues of MFG-E8-deficient mice exposed to pristane. In patients with SLE and mice with pristane-induced lupus, neutrophil accumulation is elevated, which depends on higher expression of the surface receptor CXCR2. After pretreatment with recombinant MFG-E8, the surface expression of CXCR2 on neutrophil is downregulated, and the MFG-E8 deletion increase CXCR2 expression by ~40%. These studies indicate that MFG-E8 reduces neutrophil migration and NETosis via downregulating surface CXCR2 expression in parallel with its role in the phagocytosis of apoptotic neutrophils, suggesting that MFG-E8 may serve as a therapeutic agent for attenuating the early inflammatory responses of SLE and protect patients from lupus-related damage.

SUBMITTER: Huang W

PROVIDER: S-EPMC5299708 | biostudies-other | 2017 Feb

REPOSITORIES: biostudies-other

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Milk fat globule-EGF factor 8 suppresses the aberrant immune response of systemic lupus erythematosus-derived neutrophils and associated tissue damage.

Huang Wei W Wu Jiyuan J Yang Huiqin H Xiong Yin Y Jiang Rui R Cui Tianpen T Ye Duyun D

Cell death and differentiation 20161021 2

Abnormal features of the systemic lupus erythematosus (SLE)-derived neutrophils, promoted aberrant immune response, have inspired new studies of the induction of autoimmunity and the development of organ damage in SLE. In this study, we explore the effect of milk fat globule-EGF factor 8 (MFG-E8) on the aberrant nitrification features in pristane-induced lupus. SLE patients and mice with pristane-induced lupus develop autoantibodies associated with MFG-E8 overproduction. However, the deletion of ...[more]

PMID: 27768123

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Project description:BackgroundB lymphocytes (B cells) are essential in humoral response, and their activation is an important first step for the production of antibodies. However, aberrant B-cell activation is common in the development and progression of autoimmune diseases including systemic lupus erythematosus (SLE), which is characterized by the generation of superfluous autoantibodies. SLE exhibits clinical manifestation such as excessive inflammation and tissue damage. This review aims to summarize the recent emerging studies on aberrant B-cell activation and the associated concurrent therapeutic targets in SLE.SummaryAberrant B-cell activation is closely associated with the pathogenesis of SLE. Among a variety of mechanisms, dysregulations of B-cell receptor (BCR), toll-like receptor (TLR), and B-cell activating factor receptor (BAFF-R) pathways are the common and dominating factors involved in aberrant B-cell activation. These aberrant signaling transductions play diverse and integrated roles in the development and the pathogenesis of SLE. Therapies targeting aberrant B-cell activation have shown promising efficacy in achieving the clinical alleviation of SLE, suggesting the discovery of new drug targets from these aberrant signaling pathways is imminent. Here, an integrated survey or review of published high-throughput sequencing database covering RNAs of B cells from SLE versus criteria-matched healthy controls highlights that reported signaling molecules in BCR pathway (VAV2, PLC-γ2), TLR pathway (TLR9, P105, IRF7, TAB1), and BAFF-R pathway (SDF-1α) are attitudinally upregulated in SLE patients. This review thus suggests the concurrent and future therapeutic targets and potential biomarkers in both basic and clinical studies of SLE.Key messagesThis review focuses on core B-cell signaling pathways, discussing the progress in the role of aberrant B-cell activation during the pathogenesis of SLE. This review also highlights the signaling molecules from published studies and database for the possible prevention and treatment targets serving the future clinical treatments of SLE.

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Milk fat globule-EGF factor 8 suppresses the aberrant immune response of systemic lupus erythematosus-derived neutrophils and associated tissue damage.

Publications

Milk fat globule-EGF factor 8 suppresses the aberrant immune response of systemic lupus erythematosus-derived neutrophils and associated tissue damage.

Similar Datasets

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