Systemic lupus erythematosus (SLE) causes damaging inflammation in multiple organs via the accumulation of immune complexes. These complexes activate plasmacytoid dendritic cells (pDCs) via toll-like receptors (TLRs), contributing to disease pathogenesis by driving the secretion of inflammatory type I interferons (IFNs). Antimalarial drugs, such as chloroquine (CQ), are TLR antagonists used to alleviate inflammation in SLE. However, they require ∼3 months of continuous use before achieving therapeutic efficacy and can accumulate in the retinal pigment epithelium with chronic use, resulting in retinopathy. We hypothesized that poly(ethylene glycol)-b-poly(propylene sulfide) filamentous nanocarriers, filomicelles (FMs), could directly deliver CQ to pDCs via passive, morphology-based targeting to concentrate drug delivery to specific immune cells, improve drug activity by increased inhibition of type I IFN, and enhance efficacy per dose. Healthy human peripheral blood mononuclear cells were treated with soluble CQ or CQ-loaded FMs, stimulated with TLR agonists or SLE patient sera, and type I IFN secretion was quantified via multi-subtype IFN-α ELISA and MX1 gene expression using real-time reverse transcription-quantitative polymerase chain reaction. Our results showed that 50 μg CQ/mg FM decreased MX1 expression and IFN-α production after TLR activation with either synthetic nucleic acid agonists or immune complex-rich sera from SLE patients. Cellular uptake and biodistribution studies showed that FMs preferentially accumulate in human pDCs and monocytes in vitro and in tissues frequently damaged in SLE patients (i.e., kidneys), while sparing the eye in vivo. These results showed that nanocarrier morphology enables drug delivery, and CQ-FMs may be equally effective and more targeted than soluble CQ at inhibiting SLE-relevant pathways.

Targeted Delivery of Chloroquine to Antigen-Presenting Cells Enhances Inhibition of the Type I Interferon Response.

<ns3:p><ns3:bold>Background: </ns3:bold>First-line defence against viral infection is contingent upon rapid detection of conserved viral structural and genomic motifs by pattern recognition receptors, followed by activation of the type I IFN response and establishment of an antiviral state. Novel antiviral functions of bone morphogenetic protein and related activin cytokines, acting in conjunction with, and independently of, type I IFN, have recently been described. How these antiviral effects are mediated and triggered by viral infection has not been defined.</ns3:p><ns3:p> <ns3:bold>Methods:</ns3:bold> Microarray and RNAseq data from hepatoma-derived cell lines stimulated with Activin A<ns3:italic> in vitro</ns3:italic> were interrogated both by pathway analysis and for evidence of IFN-stimulated gene induction. Liver tissue obtained from patients with chronic HCV were examined by real-time quantitative polymerase chain reaction (RT-qPCR) for evidence of Activin A induction. Activin expression by peripheral blood mononuclear cells exposed to nucleic acid analogues was quantified by RT-qCR, whereas induction dynamics in acute infection was investigated in <ns3:italic>in vitro</ns3:italic> Sendai virus infection and a murine influenza A.</ns3:p><ns3:p> <ns3:bold>Results:</ns3:bold> Transcriptomic analyses delineated strikingly congruent patterns of gene regulation in hepatocytes stimulated with recombinant Activin A and IFNα <ns3:italic>in vitro</ns3:italic>. Activin A mRNA, encoded by <ns3:italic>INHBA</ns3:italic>, is induced upon activation of RIG-I, MDA5 and TLR7/8 viral nucleic acid sensors <ns3:italic>in vitro</ns3:italic>, across multiple cell lines and in human peripheral blood mononuclear cells. <ns3:italic>In vivo</ns3:italic>, imurine influenza A also upregulated <ns3:italic>Inhba </ns3:italic>mRNA in the lung; this local upregulation of <ns3:italic>Inhba</ns3:italic> is retained in MAVS knockout mice, indicating roles for non-RIG-I-like receptors in its induction. Activin induction and signalling were also detectable in patients with chronic viral hepatitis.</ns3:p><ns3:p> <ns3:bold>Conclusions: </ns3:bold>These data suggest Activin A is triggered in parallel with type I IFN responses and can trigger related antiviral effector functions, with implications for the development of targeted antiviral therapies and revealing novel facets of Activin biology.</ns3:p> 

Innate triggering and antiviral effector functions of Activin A

Systemic lupus erythematosus (SLE) causes damaging inflammation in multiple organs via the accumulation of immune complexes. These complexes activate plasmacytoid DCs (pDCs) via TLR7 and TLR9, contributing to disease pathogenesis by driving secretion of inflammatory type I IFNs. Antimalarial drugs, such as chloroquine (CQ), are TLR antagonists used to alleviate inflammation in SLE. However, they require ~3 months of continuous use before achieving therapeutic efficacy and can accumulate in the retinal pigment epithelium with chronic use resulting in retinopathy. We hypothesized that poly(ethylene glycol)-b-poly(propylene sulfide) (PEG-b-PPS) filamentous nanocarriers, filomicelles (FMs) could improve drug activity and reduce toxicity by directly delivering CQ to pDCs via passive, morphology-based targeting. Healthy human PBMCs were treated with soluble CQ or CQ-loaded FMs, stimulated with TLR agonists or SLE patient sera, and type I IFN secretion was quantified via multi-subtype IFN- ELISA and MX1 gene expression using real-time RT-qPCR. Our results showed that 50 {micro}g CQ/mg FM decreased MX1 expression and IFN- production after TLR activation with either synthetic nucleic acid agonists or immune complex rich sera from SLE patients. Cellular uptake and biodistribution studies showed that FMs preferentially accumulate in human pDCs in vitro and in tissues frequently damaged in SLE patients (i.e., liver and kidneys) while sparing the eye in vivo. These results showed that nanocarrier morphology enables drug delivery, and CQ-FMs may be equally effective and more targeted than soluble CQ at inhibiting SLE-relevant pathways.

/pdf/targeted-delivery-of-chloroquine-to-plasmacytoid-dendritic-14m0glmqj9.pdf

Targeted Delivery of Chloroquine to Plasmacytoid Dendritic Cells Enhances Inhibition of the Type I Interferon Response

First-line defence against viral infection is contingent upon rapid detection of conserved viral structural and genomic motifs by germline-encoded pattern recognition receptors, followed by activation of the type I IFN system and establishment of an intracellular antiviral state. Novel antiviral functions of bone morphogenetic protein and related activin cytokines, acting in conjunction with, and independently of, type I IFN, have recently been described. Activin A mediates multiple innate and adaptive immune functions – including antiviral effects. However, how such effects are mediated and how activin might be triggered by viral infection have not been defined. Here we addressed this in vivo and in vitro, in humans and mice. Transcriptomic analyses delineated strikingly congruent patterns of gene regulation in hepatocytes stimulated with recombinant activin A and IFNα in vitro. Activin A mRNA, encoded by INHBA, is induced upon activation of RIG-I, MDA5 and TLR7/8 viral nucleic acid sensors in vitro, across multiple cell lines and in human peripheral blood mononuclear cells. In vivo, infection of mice with influenza A also upregulated Inhba mRNA in the lung; this local upregulation of Inhba is retained in MAVS knockout mice, indicating a role for non-RIG-I-like receptors in its induction. Activin induction and signalling were also detectable in patients with chronic viral hepatitis. Together, these data suggest Activin A is triggered in parallel with type I IFN responses and can trigger related antiviral effector functions. This model has implications for the development of targeted antiviral therapies, in addition to revealing novel facets of activin biology.

/pdf/innate-triggering-and-antiviral-effector-functions-of-3aydvof1hb.pdf

Innate triggering and antiviral effector functions of activin A

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Innate triggering and antiviral effector functions of activin A