Hydroxychloroquine is associated with impaired interferon-alpha and tumor necrosis factor-alpha production by plasmacytoid dendritic cells in systemic lupus erythematosus

Abstract

IntroductionPlasmacytoid dendritic cells (pDCs) constitutively express two members of the Toll-like receptor (TLR) family, TLR-9 and TLR-7, through which they can be stimulated to produce high levels of interferon (IFN)-α, a key mediator of the pathogenesis of systemic lupus erythematosus (SLE). Given the known efficacy of hydroxychloroquine (HCQ) in the treatment of SLE, we examined its ability to inhibit such pDC function in vivo.MethodsPeripheral blood mononuclear cells (PBMCs) from SLE subjects treated or not with HCQ and from healthy controls were stimulated with the TLR-9 agonist, CpG oligodeoxynucleotides (CpG-A ODN)-2216, and the TLR-7 agonist, imiquimod. The proportion of monocytes, B cells, myeloid dendritic cells, pDCs, and natural killer (NK) cells producing IFN-α and tumor necrosis factor alpha (TNF-α) was then analyzed by multiparameter flow cytometry.ResultsAfter TLR-9/7 stimulation in both SLE and healthy subjects, significant production of IFN-α and TNF-α was only observed in pDCs. TLR-7 and TLR-9 induced IFN-α and TNF-α production by pDCs from subjects with SLE was decreased relative to that found in controls (TLR-9/IFN-α, P < 0.0001; TLR-9/TNF-α P < 0.0001; TLR-7/TNF-α P = 0.01). TLR-9 and TLR-7 induced IFN-α and TNF-α production by pDCs was severely impaired in 36% (TLR-9) and 33% (TLR-7) of SLE subjects. In almost all cases, these subjects were being treated with HCQ (HCQ vs. no HCQ: impaired TLR-9/IFN-α, P = 0.0003; impaired TLR-7/IFN-α, P = 0.07; impaired TLR-9/TNF-α, P < 0.009; impaired TLR-7/TNF-α, P < 0.01).ConclusionsTreatment with HCQ is associated with impaired ability of pDCs from subjects with SLE to produce IFN-α and TNF-α upon stimulation with TLR-9 and TLR-7 agonists.

Why are kids with lupus at an increased risk of cardiovascular disease?

“…It is thought to block Toll-like receptors (TLR), reducing the activation of dendritic cells. In vitro plasmacytoid dendritic cells from SLE patients treated with hydroxychloroquine showed an impaired ability to produce interferon-α (IFN-α) and tumor necrosis factor-α when stimulated with TLR-9 and TLR-7 agonists [152]. In addition to its efficacy in preventing flares of SLE, there is epidemiological evidence [74,98,153] that it may be cardioprotective, possibly by improving the lipoprotein profile [154] and improving vessel elasticity [155].…”

Effects of Hydroxychloroquine on Proteinuria in Immunoglobulin A Nephropathy

“…HCQ is a weak base with the ability to increase intracellular pH; thus, HCQ may alter lysosome stability, suppress antigen presentation and cytokine synthesis, and inhibit TLR stimulation in vivo [15-17]. Theoretically, HCQ can suppress innate immune system activation by mucosal antigens via TLR inhibition, which results in reduced mucosal IgA-committed B cell proliferation [18].…”

“…In vitro and in vivo studies have shown that HCQ suppresses the production of numerous cytokines, including IL-6, IFN-α, TNF-α, by peripheral blood mononuclear cells and plasmacytoid dendritic cells [12, 15, 20-22]. Suzuki et al [23] found that treating cultured IgA1-secreting cells with IL-6 increased the production of Gd-IgA1 and the degree of the galactose deficiency by enhancing the already elevated activity of N-acetylgalactosamine (GalNAc)-specific sialyltransferase, which increased the sialylation of terminal GalNAc.…”

Antimalarial drugs inhibit IFNα-enhanced TNFα and STAT4 expression in monocytes: Implication for systemic lupus erythematosus

“…Recently, it has been observed that the significant clinical improvement in SLE patients after hydroxychloroquine therapy correlated with reductions in IFNa levels [50]. Furthermore, treatment with hydroxychloroquine was associated with an impaired ability of pDCs from subjects with SLE to produce IFNa and TNFa upon stimulation with TLR7/9 agonists [51].…”