CD47-Signal Regulatory Protein-Alpha Interaction Potentiates Proinflammatory Response in Systemic Lupus Erythematosus.

Background/Purpose: Systemic lupus erythematosus (SLE) is a chronic inflammatory disease mediated by unbalanced activation of innate and adaptive immune cells with subsequent uncontrolled inflammation and organ damages. An important regulatory receptor on monocyte is signal regulatory protein alpha (SIRP-alpha) that interact with CD47. This study was aimed to investigate as to whether CD47 contributes to altered proinflammatory response in SLE.

Methods: Expression of CD47 and SIRP-alpha on peripheral blood mononuclear cells (PBMCs) from SLE patients and healthy controls (HCs) were examined using flow cytometry analysis. Effect of SLE serum, recombinant interferon (IFN)-alpha, and tumor necrosis factor (TNF)-alpha on CD47 expression was investigated. Monocytes and THP1 cells were stimulated with lipopolysaccharide (LPS) with or without pretreatment with anti-CD47 antibody, and TNF-alpha production and mitogen-activated protein kinase (MAPK) and NFkB signaling were examined. Sera from HCs and SLE patients were screened for autoantibodies directed against CD47 using ELISA.

Results: A total of 25 patients and 16 healthy controls (HCs) were enrolled. CD47 expression on monocytes was higher in SLE patients vs. HCs (p < 0.001) and it correlated with SLE disease activity (Spearman rho = 0.467, p = 0.019). CD47 expression was upregulated by serum from SLE patients with higher disease activity and exogenous IFN-alpha but not by exogenous TNF-alpha. Pretreatment of monocytes with anti-CD47 antibody potentiated TNF-alpha production in response to LPS by 16.1 folds as compared to 8.5 folds after stimulation with LPS alone, whereas no to little TNF-alpha was produced after treatment with anti-CD47 alone. CD47 activation induced MAPK but not NFkB signaling. Finally, autoantibodies against CD47 were detected in 30.7% of SLE patients.

Conclusion: To the best our knowledge, this report is the first to show that CD47 expression is upregulated during active SLE and potentiates proinflammatory response in SLE. Targeting CD47-SIPR-alpha interaction might offer a novel therapeutic opportunity in SLE treatment.

Figure. A. CD47 expression on monocytes correlated with disease activity. B. CD47 on monocytes was upregulated after treatment with serum from patients with low (n=6) and higher (n=4) disease activity or healthy controls (HC). C. Monocytes were pretreated with anti-CD47 antibody and were stimulated with LPS (3 ng/mL) for 5 hours and TNF-alpha production was measured.