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Sodium valproate modulates immune response by alternative activation of monocyte-derived macrophages in systemic lupus erythematosus

Abstract

The anti-inflammatory role of macrophages in apoptotic cells (ACs) clearance is involved in Systemic Lupus Erythematosus (SLE) pathogenesis. The efferocytic capability of macrophages is altered by M1/M2 polarization. Histone deacetylase inhibitors (HDACi) are proposed to enhance the expansion of M2 macrophages. Sodium valproate (VPA) is an HDACi with different anti-inflammatory properties. Here, we aimed to investigate the effects of HDACi by VPA on the polarization of monocyte-derived macrophages (MDMs) and regulating the expression of anti-inflammatory cytokines in SLE. We studied the ex vivo alterations of MDMs among 15 newly diagnosed SLE patients and 10 normal subjects followed by ACs and VPA treatments. M1/M2 polarization was assessed by expression of CD86/CD163, IL1-β, IDO-1, and MRC-1 among treated and non-treated MDMs. We also evaluated the production of IL-10, IL-12, TGF-β1, and TNF-α cytokines in the cell culture supernatants. CD163 was overexpressed upon VPA treatment, while CD86 showed no significant change. IL1-β and IDO-1 genes were significantly downregulated, and the mRNA expression of MRC-1 was increased among VPA-treated MDMs of SLE patients. The anti-inflammatory cytokines (IL-10 and TGF-β1) were overproduced while TNF-α level was decreased in response to VPA. The population of classically activated macrophages was more prevalent among SLE patients and efferocytosis was defected. VPA could successfully enhance the anti-inflammatory immune response through alternative activation of MDMs in SLE patients.

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Fig. 1: Flowcytometric immunophenotyping of M1 (CD86) and M2 (CD163) cell surface markers
Fig. 2: ELISA cytokine assay
Fig. 3: The mRNA expression of IL1-β, IDO-1, and MRC-1
Fig. 4: Quantifying the efficiency of alternative activation

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Acknowledgments

We would like to acknowledge Dr. S Zhand, Dr. Ayyoob Khosravi, and Mrs. Haydari for their technical and scientific consults.

Funding

This article was derived from a research project funded by Students Research Committee at Golestan University of Medical Sciences, Gorgan, Iran (Grant Code: 930618118).

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Correspondence to Sima Sedighi or Ali Memarian.

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This article contains studies with human participants. The present study was approved by ethics committee, Golestan University of Medical Sciences, Gorgan, Iran (Code of Ethics: 1479179306194). An informed consent following the declaration of Helsinki was signed and taken from all participants.

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Mohammadi, S., Saghaeian-Jazi, M., Sedighi, S. et al. Sodium valproate modulates immune response by alternative activation of monocyte-derived macrophages in systemic lupus erythematosus. Clin Rheumatol 37, 719–727 (2018). https://doi.org/10.1007/s10067-017-3922-0

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Keywords

  • Histone deacetylase inhibitor
  • Macrophage polarization
  • Sodium valproate
  • Systemic lupus erythematosus