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.

The Role of Monocytes and Macrophages in Autoimmune Diseases: A Comprehensive Review

“…Several molecules and pathways have been suggested to be associated with controlling polarization and inflammatory profiles of Mϕ. For example, using MDMs of normal subjects and SLE patients, Saeed et al found that epigenetic modification is partly responsible for the Mϕ polarization profile in SLE (225). Their data showed that sodium valproate, an histone deacetylase inhibitor, can potently induce the alternative activation of Mo-Mϕ ex vivo and inhibit the pro-inflammatory profile of these cells when stimulated by apoptotic cells in vitro (225).…”

Exploring the Drug Repurposing Versatility of Valproic Acid as a Multifunctional Regulator of Innate and Adaptive Immune Cells

“…This was accompanied by an increase in both IL-10 and TGF- β and reduced levels of IL-1 β and TNF- α . These phenotypic changes could be an adjuvant for the treatment of autoimmune diseases [76].…”

Angiotensin II induces RAW264.7 macrophage polarization to the M1‑type through the connexin 43/NF‑κB pathway

“…Autopsies of patients with atherosclerosis revealed that a large number of macrophages, lymphocytes and foam cells are found in the coronary plaque, and the ratio of macrophages and lymphocytes is largest in the rupture plaque (25). Macrophages are mainly divided into two different subtypes: M1 and M2, which are predominantly located in unstable plaques and stable plaque tissues, respectively (5,6). It has previously been reported that iNOS, TNF-α, il-1β, IL-6, IL-12 and CD86 are major markers of M1-type macrophages (27).…”

“…For example, in one previous study, autopsies of patients with atherosclerosis discovered the accumulation of a large number of macrophages, lymphocytes and foam cells in the coronary artery plaques (2). Macrophages are mainly divided into two different subtypes: M1-type macrophages are mainly found in unstable plaques, whereas M2-type macrophages are predominantly found in stable plaque tissue (5,6). During the development of the disease, various external factors affect macrophages, and depending on the M1/M2 polarization status, the corresponding inflammatory process is highly different (5,7).…”

“…Macrophages are mainly divided into two different subtypes: M1-type macrophages are mainly found in unstable plaques, whereas M2-type macrophages are predominantly found in stable plaque tissue (5,6). During the development of the disease, various external factors affect macrophages, and depending on the M1/M2 polarization status, the corresponding inflammatory process is highly different (5,7). Binesh et al (7) found that pro-inflammatory macrophages (M1-type) were expressed in atherogenic diet-induced aorta, while anti-inflammatory macrophages (M2-type) were expressed in diosgenin-treated aorta.…”