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.

E3 ligase FBXW7 aggravates TMPD-induced systemic lupus erythematosus by promoting cell apoptosis

“…The Lysm-Cre mice could also experience an FBXW7 deletion in neutrophils, and neutrophil apoptosis plays a vital role in SLE progression. 20 Therefore, we isolated bone marrow neutrophils and performed an apoptosis assay; the neutrophil result was similar to that of the macrophages (Fig. 5c, d), indicating that both macrophage and neutrophil apoptosis could contribute to lupus progression.…”

“…In the TMPD-induced mouse SLE model, cell apoptosis is a key event for the initiation of mouse SLE and a potential source of autoantigens. 20,21 We found more apoptotic cells in FBXW7 f/f mice than in Lysm + FBXW7 f/f mice (Fig. 3a, b).…”

“…19 TMPD-induced peritoneal cell apoptosis in vivo is a crucial event in the self-tolerance breaking and pathogenesis of SLE, which are considered a critical source of autoantigens. 20,21 Two weeks after the TMPD injection, all cells were collected from the peritoneal cavity, and the apoptotic cells were analyzed by flow cytometry. The proportion of apoptotic cells was increased after the TMPD treatment ( Fig.…”

“…[12][13][14][15][16] 2, 6, 10, 14tetramethylpentadecane (TMPD), which is also known as pristine, has been widely used to induce murine models of SLE. [17][18][19][20] TMPDtreated mice show many clinical features of human lupus, including glomerulonephritis, arthritis, immune complex deposition, and autoantibody production. 19 TMPD-induced apoptosis is considered a critical initial event in the pathogenesis of SLE, which depends on IFN-I signaling.…”

MFG‐E8 regulates inflammation and apoptosis in tendon healing, and promotes tendon repair: A histological and biochemical evaluation

“…Increasing evidence points to the essential function of MFG‐E8 in diverse physiological functions such as inflammation and apoptosis . Macrophages participate in tissue regeneration by regulating inflammation and angiogenesis.…”