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Parkinson’s disease (PD) is characterized by neurodegeneration of nigral-striatal neurons in parallel with the formation of intra-neuronal α-synuclein aggregates, and these processes are exacerbated by neuro-inflammation. All 3 components of PD pathology are potentially treatable with biologics. Neurotrophins, such as glial derived neurotrophic factor or erythropoietin, can promote neural repair. Therapeutic antibodies can lead to disaggregation of α-synuclein neuronal inclusions. Decoy receptors can block the activity of pro-inflammatory cytokines in brain. However, these biologic drugs do not cross the blood–brain barrier (BBB). Biologics can be made transportable through the BBB following the reengineering of the biologic as an IgG fusion protein, where the IgG domain targets an endogenous receptor-mediated transcytosis (RMT) system within the BBB, such as the insulin receptor or transferrin receptor. The receptorspecific antibody domain of the fusion protein acts as a molecular Trojan horse to ferry the biologic into brain via the BBB RMT pathway. This review describes the re-engineering of all 3 classes of biologics (neurotrophins, decoy receptor, therapeutic antibodies) for BBB delivery and treatment of PD. Targeting the RMT pathway at the BBB also enables non-viral gene therapy of PD using lipid nanoparticles (LNP) encapsulated with plasmid DNA encoding therapeutic genes. The surface of the lipid nanoparticle is conjugated with a receptor-specific IgG that triggers RMT of the LNP across the BBB in vivo. [ABSTRACT FROM AUTHOR]

Parkinson’s disease (PD) is characterized by neurodegeneration of nigral-striatal neurons in parallel with the formation of intra-neuronal α-synuclein aggregates, and these processes are exacerbated by neuro-inflammation. All 3 components of PD pathology are potentially treatable with biologics. Neurotrophins, such as glial derived neurotrophic factor or erythropoietin, can promote neural repair. Therapeutic antibodies can lead to disaggregation of α-synuclein neuronal inclusions. Decoy receptors can block the activity of pro-inflammatory cytokines in brain. However, these biologic drugs do not cross the blood–brain barrier (BBB). Biologics can be made transportable through the BBB following the re-engineering of the biologic as an IgG fusion protein, where the IgG domain targets an endogenous receptor-mediated transcytosis (RMT) system within the BBB, such as the insulin receptor or transferrin receptor. The receptor-specific antibody domain of the fusion protein acts as a molecular Trojan horse to ferry the biologic into brain via the BBB RMT pathway. This review describes the re-engineering of all 3 classes of biologics (neurotrophins, decoy receptor, therapeutic antibodies) for BBB delivery and treatment of PD. Targeting the RMT pathway at the BBB also enables non-viral gene therapy of PD using lipid nanoparticles (LNP) encapsulated with plasmid DNA encoding therapeutic genes. The surface of the lipid nanoparticle is conjugated with a receptor-specific IgG that triggers RMT of the LNP across the BBB in vivo.

Background: Decoy receptor 3 (DcR3) belongs to the tumor necrosis factor (TNF) receptor superfamily and neutralizes TNF ligands, including FasL and TRAIL, to prevent T activation during T-cell priming. However, the cellular mechanisms underlying acute cellmediated rejection (ACMR) remain unknown. Methods: We generated DcR3 transgenic (Tg) mice and mice with high DcR3 expression (HDE) to study both in vivo and in vitro. FasR RNA knockdown in immortalized CD4+CD8+ T-cells was used to survey the role of DcR3 on FasR/Fas-associated protein with death domain (FADD)/caspase 8 pathway and its cross-link to TNF receptor-associated factor 1 (TNFR1)-associated death domain protein (TRADD) in suppressing TNFR1. TNF/TRADD knockout mice were used to show the importance of TNF adaptor protein. Results: DcR3.Fc suppressed C57BL/6 female T-cell activation and transformation into CD4+CD69+, CD4+CD44+, and CD4+CD25+Foxp3+ when compared with isotype IgG1 and its co-treatment with FasL/TRAIL after exposing to bone marrow-derived dendritic cells (BMDCs) that carried alloantigen with male H-Y and minor antigenic determinant. Interleukin-17 and interferon-g productions by BMDC-activated T-cells were lowered after co-treating with DcR3.Fc. DcR3.Fc induced effector T-cells (Teffs) and was susceptible to FasR-mediated apoptosis through the FADD/TRADD/caspase 8 pathway. After exposing to DcR3.Fc, TRADD was silenced, likely turning down the inflammatory response. The systemic effects of DcR3 Tg mice and HDE phenotype induced by the promoter of cytomegalovirus not only attenuated ACMR severity but also ameliorated the high serum creatinine and blood urea nitrogen levels even with high T-cell exposure frequencies. Besides this, DcR3 has minor biological effects on both MHC-matched and MHCmismatched models. Conclusions: High DcR3 doses protect renal tubular epithelial cells from acute T-cell attack during the T-cell priming stage via interfering with TNF ligand-mediated reverse signaling and possibly promoting Teff apoptosis through FasR upregulation. Our findings supported that the decoy receptor is involved in T-cell modulation in kidney transplant rejection. [ABSTRACT FROM AUTHOR]

Background: Neuronal apoptosis involved in secondary injury following traumatic brain injury (TBI) significantly contributes to the poor outcomes of patients with TBI. The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can selectively induce apoptosis of tumor cells. Hypoxia factor (HIF) 1α is a controversial factor that mediates the neuronal apoptotic pathway. Herein, we hypothesize that HIF-1α may mediate the TRAIL-induced neuronal apoptosis after TBI.Methods: We used Western blots and immunofluorescence to study the expression and cell localization of TRAIL and death receptor 5 (DR5) after TBI in rats. Soluble DR5 (sDR5) administration was used to block the TRAIL-induced neuronal death and neural deficits. HIF-1α inhibitor 2ME and agonist DMOG were used to study the role of HIF-1α in TRAIL-induced neuronal death. Meanwhile, HIF-1α siRNA was used to investigate the role of HIF-1α in TRAIL-induced neuronal death in vitro.Results: The expressions of microglia-located TRAIL and neuron-located DR5 were significantly upregulated after TBI. sDR5 significantly attenuated TRAIL-induced neuronal apoptosis and neurological deficits. 2ME decreased neuronal apoptosis, lesion area, and brain edema and improved neurological function via increased expression of TRAIL decoy receptor 1 (DcR1), which inhibited TRAIL-induced apoptosis after TBI. The administration of DMOG produced the opposite effect than did 2ME. Similarly, HIF-1α siRNA attenuated TRAIL-induced neuronal death via increased DcR1 expression in vitro.Conclusion: Our findings suggested that the TRAIL/DR5 signaling pathway plays an important role after neuronal apoptosis after TBI. HIF-1α mediates TRAIL-induced neuronal apoptosis by regulating DcR1 expression following TBI.

Members of the IL-1 family play a key role in innate and adaptive immunity and in the pathogenesis of diverse diseases. Members of IL-1R like receptor (ILR) family include signalling molecules and negative regulators. The latter include decoy receptors (IL-1RII; IL-18BP) and "receptors" with regulatory function (TIR8/SIGIRR; IL-1RAcPb; DIGIRR). Structural considerations suggest that also TIGIRR-1 and IL-1RAPL may have regulatory function. The presence of multiple pathways of negative regulation of members of the IL-1/IL-1R family emphasizes the need for a tight control of members of this fundamental system.

Members of the IL-1 family play a key role in innate and adaptive immunity and in the patho genesis of diverse diseases. Members of IL-1R like receptor (ILR) family include signaling molecules and negative regulators.The latter include decoy receptors (IL-1RII; IL-18BP) and "receptors" with regulatory function (TIR8/SIGIRR; IL-1RAcPb; DIGIRR). Structural con siderations suggest that also TIGIRR-1 and IL-1RAPL may have regulatory function. The presence of multiple pathways of negative regulation of members of the IL-1/IL-1R family emphasizes the need for a tight control of members of this fundamental system. [ABSTRACT FROM AUTHOR]

This section introduces a series of articles about interleukin-1 (IL) family of ligands including the biology of IL-18 as well as its role in human disease, hypotheses on the mechanisms of externalization of IL-1 family members, and the dichotomous functions of IL-1 family members.