Increased IFN-α production contributes to the pathogenesis of infectious and autoimmune diseases. Plasmacytoid dendritic cells (pDCs) from females produce more IFN-α upon TLR7 stimulation than pDCs from males, yet the mechanisms underlying this difference remain unclear. In this article, we show that basal levels of IFN regulatory factor (IRF) 5 in pDCs were significantly higher in females compared with males and positively correlated with the percentage of IFN-α–secreting pDCs. Delivery of recombinant IRF5 protein into human primary pDCs increased TLR7-mediated IFN-α secretion. In mice, genetic ablation of the estrogen receptor 1 (Esr1) gene in the hematopoietic compartment or DC lineage reduced Irf5 mRNA expression in pDCs and IFN-α production. IRF5 mRNA levels furthermore correlated with ESR1 mRNA levels in human pDCs, consistent with IRF5 regulation at the transcriptional level by ESR1. Taken together, these data demonstrate a critical mechanism by which sex differences in basal pDC IRF5 expression lead to higher IFN-α production upon TLR7 stimulation in females and provide novel targets for the modulation of immune responses and inflammation.

As the world is severely affected by COVID-19 pandemic, the use of chloroquine and hydroxychloroquine in prevention or for the treatment of patients is allowed in multiple countries but remained at the center of much controversy in recent days. This review describes the properties of chloroquine and hydroxychloroquine, and highlights not only their anti-viral effects but also their important immune-modulatory properties and their well-known use in autoimmune diseases, including systemic lupus and arthritis. Chloroquine appears to inhibit in vitro SARS virus' replication and to interfere with SARS-CoV2 receptor (ACE2). Chloroquine and hydroxychloroquine impede lysosomal activity and autophagy, leading to a decrease of antigen processing and presentation. They are also known to interfere with endosomal Toll-like receptors signaling and cytosolic sensors of nucleic acids, which result in a decreased cellular activation and thereby a lower type I interferons and inflammatory cytokine secretion. Given the antiviral and anti-inflammatory properties of chloroquine and hydroxychloroquine, there is a rational to use them against SARS-CoV2 infection. However, the anti-interferon properties of these molecules might be detrimental, and impaired host immune responses against the virus. This duality could explain the discrepancy with the recently published studies on CQ/HCQ treatment efficacy in COVID-19 patients. Moreover, although these treatments could be an interesting potential strategy to limit progression toward uncontrolled inflammation, they do not appear per se sufficiently potent to control the whole inflammatory process in COVID-19, and more targeted and/or potent therapies should be required at least in add-on.

Background.Human immunodeficiency virus (HIV) controllers spontaneously control viremia and CD4 T-cell depletion in contrast to viremic patients. After HIV exposure, plasmacytoid dendritic cells (pDCs) produce high levels of interferon alpha (IFN-α) and express the apoptotic ligand TRAIL (tumor necrosis factor–related apoptosis inducing ligand). Simian models have shown that prolonged high levels of IFN-α production could be responsible for AIDS progression. Methods.We studied pDC activation in response to human immunodeficiency virus (HIV) using flow cytometry and 3D microscopy. Results.We show here that pDCs from controller patients produced higher levels of IFN-α in response to HIV than pDCs from viremic patients but similar levels to pDCs from healthy donors. Because binding of HIV to CD4 is essential for pDC activation, the low CD4 expression by pDCs from viremic patients may explain the weak IFN-α response to HIV. Three-dimensional microscopy revealed that pDCs from controllers and healthy donors expressed intracellular TRAIL that is relocalized to the membrane after HIV exposure. In contrast, pDCs from viremic patients expressed membrane TRAIL without any stimulation. Conclusions.We demonstrate that, in response to HIV, pDCs from controller patients produce IFN-α, express membrane TRAIL, and induce apoptosis of T-cell lines.

CXCR4 engagement by amines leads to the control of IFN signaling in pDCs and opens new therapeutic perspectives in Lupus patients.

Dengue displays a broad spectrum of clinical manifestations that may vary from asymptomatic to severe and even fatal features. Plasma leakage/hemorrhages can be caused by a cytokine storm induced by monocytes and dendritic cells during dengue virus (DENV) replication. Plasmacytoid dendritic cells (pDCs) are innate immune cells and in response to virus exposure secrete IFN-α and express membrane TRAIL (mTRAIL). We aimed to characterize pDC activation in dengue patients and their function under DENV-2 stimulation in vitro. Flow cytometry analysis (FCA) revealed that pDCs of mild dengue patients exhibit significantly higher frequencies of mTRAIL compared to severe cases or healthy controls. Plasma levels of IFN-α and soluble TRAIL are increased in mild compared to severe dengue patients, positively correlating with pDC activation. FCA experiments showed that in vitro exposure to DENV-2 induced mTRAIL expression on pDC. Furthermore, three dimension microscopy highlighted that TRAIL was relocalized from intracellular compartment to plasma membrane. Chloroquine treatment inhibited DENV-2-induced mTRAIL relocalization and IFN-α production by pDC. Endosomal viral degradation blockade by chloroquine allowed viral antigens detection inside pDCs. All those data are in favor of endocytosis pathway activation by DENV-2 in pDC. Coculture of pDC/DENV-2-infected monocytes revealed a dramatic decrease of antigen detection by FCA. This viral antigens reduction in monocytes was also observed after exogenous IFN-α treatment. Thus, pDC effect on viral load reduction was mainly dependent on IFN-α production This investigation characterizes, during DENV-2 infection, activation of pDCs in vivo and their antiviral role in vitro. Thus, we propose TRAIL-expressing pDCs may have an important role in the outcome of disease. Dengue is an important endemic tropical disease to which there are no specific therapeutics or approved vaccines. Currently several aspects of pathophysiology remain incompletely understood. A crucial cellular population for viral infections, the plasmacytoid dendritic cells (pDCs) was analyzed in this study. The authors found an in vivo association between the activation state of pDCs and the disease outcome. Membrane TNF-related apoptosis inducing ligand (TRAIL) expressing pDCs, representing activated pDCs, were found in higher frequency in milder cases of dengue than severe cases or healthy individuals. Detection of antiviral cytokine interferon-alpha (IFN-α) and soluble TRAIL positively correlated with pDC activation. Dengue virus (DENV) serotype-2 was able to directly activate pDCs in vitro. Under DENV stimulation TRAIL was relocalized from intracellular to pDC plasma membrane and IFN-α was highly produced. The authors suggest an endocytosis-dependent pathway for DENV-induced pDC activation. It is also highlighted here a role for exogenous IFN-α and pDCs in reducing viral replication in monocytes, one of DENV main target cells. These findings may contribute in the future to the establishment of good prognostic immune responses together with clinical manifestations/warning signs.

TRIM8 and Pin1 oppositely control IRF7-induced interferon production.