Multiple Roles of Peripheral Immune System in Modulating Ischemia/Hypoxia-Induced Neuroinflammation

Given combined efforts of neuroscience and immunology, increasing evidence has revealed the critical roles of the immune system in regulating homeostasis and disorders of the central nervous system (CNS). Microglia have long been considered as the only immune cell type in parenchyma, while at the interface between CNS and the peripheral (meninges, choroid plexus, and perivascular space), embryonically originated border-associated macrophages (BAMs) and multiple surveilling leukocytes capable of migrating into and out of the brain have been identified to function in the healthy brain. Hypoxia-induced neuroinflammation is the key pathological procedure that can be detected in healthy people at high altitude or in various neurodegenerative diseases, during which a very thin line between a beneficial response of the peripheral immune system in maintaining brain homeostasis and a pathological role in exacerbating neuroinflammation has been revealed. Here, we are going to focus on the role of the peripheral immune system and its crosstalk with CNS in the healthy brain and especially in hypobaric or ischemic hypoxia-associated neuroinflammation.

Uveitis: Molecular Pathogenesis and Emerging Therapies

The profound impact that vision loss has on human activities and quality of life necessitates understanding the etiology of potentially blinding diseases and their clinical management. The unique anatomic features of the eye and its sequestration from peripheral immune system also provides a framework for studying other diseases in immune privileged sites and validating basic immunological principles. Thus, early studies of intraocular inflammatory diseases (uveitis) were at the forefront of research on organ transplantation. These studies laid the groundwork for foundational discoveries on how immune system distinguishes self from non-self and established current concepts of acquired immune tolerance and autoimmunity. Our charge in this review is to examine how advances in molecular cell biology and immunology over the past 3 decades have contributed to the understanding of mechanisms that underlie immunopathogenesis of uveitis. Particular emphasis is on how advances in biotechnology have been leveraged in developing biologics and cell-based immunotherapies for uveitis and other neuroinflammatory diseases.

Systemic sterile induced-co-expression of IL-12 and IL-18 drives IFN-γ-dependent activation of microglia and recruitment of MHC-II-expressing inflammatory monocytes into the brain

ABSTRACTThe development of neuroinflammation, as well as the progression of several neurodegenerative diseases, has been associated with the activation and mobilization of the peripheral immune system due to systemic inflammation. However, the mechanism by which this occurs remains unclear. Herein, we addressed the effect of systemic, endotoxin-free induced-co-expression of IL-12 and IL-18 in the establishment of a novel cytokine-mediated model of neuroinflammation. Following peripheral hydrodynamic shear of IL-12 plus IL-18 cDNAs in C57BL/6 mice, we induced systemic and persistent level of IL-12, which in turn promoted the elevation of circulating pro-inflammatory cytokines TNF-α and IFN-γ, accompanied with splenomegaly. Moreover, even though we identified an increased gene expression of both TNF-α and IFN-γ in the brain, only TNF-α was shown to be dispensable, revealing an IFN-γ-dependent activation of microglia and the recruitment of leukocytes, particularly of highly activated inflammatory monocytes. Taken together, our results argue for a systemic cytokine-mediated establishment and development of neuroinflammation, having identified IFN-γ as a potential target for immunotherapy.

FRI0328 PROFILING OF THE IMMUNE COMPARTMENT IN THE TISSUE ENVIRONMENT OF PSORIATIC ARTHRITIS USING RNASEQ

Background:Psoriasis is a chronic inflammatory disease of the skin with a reported prevalence of 0.09-11.4% of the population (1). 1 in 4 psoriasis patients also have psoriatic arthritis (PsA) (2), with additional joint involvement that can be associated with significant morbidity. Despite its relative commonness, the aetiology of psoriasis is not well understood, and there is no cure for this disease. Additionally, up to 30% of PsA patients with active disease are recalcitrant to treatment. Thus it remains a prerogative to understand the immune mechanisms contributing to the development of the disease in order to inform strategies for novel therapies.Objectives:Our aim was to identify perturbations in local tissue immune networks that could contribute to the pathology of psoriasis and psoriatic arthritis. We hypothesise that psoriasis is driven by a disrupted tissue microenvironment, which then provides cues to a susceptible peripheral immune system to drive pathology. Thus as the first part of our study, we investigated the transcriptional profiles of normal and lesional skin.Methods:Skin punch biopsies were obtained from both lesional and morphologically normal skin of 4 PsA patients with active disease. CD45+ cells were isolated using magnetic enrichment for RNA purification and subsequent RNAseq. Differently expressed genes (DEG) were identified and pathway analysis performed using the integrated Differential Expression and Pathway (iDEP) analysis tool. Gene set enrichment analysis was performed using GSEA.Results:Transcriptomic analyses of skin revealed that lesional skin, compared to non-lesional sites, was enhanced for expression of genes associated with immune processes (including genes such as such asIL17A,FCN1, andCTLA4) anti-microbial responses (such asDEF4BAandS100A8) and immune cell chemotaxis (notablyCXCL13andSELPLG), suggesting a possible inflammatory response to skin microbiota. Interestingly, lesional skin showed a deficiency in expression of genes associated with tRNA metabolic processes (includingAARS,YARS, and other aminoacyl tRNA synthetases), suggesting a possible defect in protein translation. Similarly, pathway analysis revealed an enrichment in humoral immune response pathways in PsA lesional skin, and a comparative deficiency in RNA metabolic pathways.Conclusion:Our transcriptional approach provides a comprehensive overview of localised immunity in psoriasis and predicts intimate interactions with the peripheral immune system. Further studies are ongoing to uncover cell types involved, as well as parallels at other disease sites (joints). These findings will facilitate the identification of novel targets for treatment of PsA.References:[1]World Health Organization (2016).Global report on psoriasis. [Online] (https://apps.who.int/iris/bitstream/handle/10665/204417/9789241565189_eng.pdf.psoriasis;jsessionid=54912784D28C9F36ECCD45471AC5775B?sequence=1,accessed 24 January 2020)[2]Alinaghi F., Calov M., Kristensen L.E., Gladman D.D, Coates L.C., Julien D., Gottlieb A.B., Gisondi P., Wu J.J., Thyssen J.P., Egeberg A. (2019) Prevalence of psoriatic arthritis in patients with psoriasis: A systemic review and meta-analysis of observational and clinical studies.Journal of the American Academy of Dermatology.,80(1), 251-265.Disclosure of Interests:Gladys Ang: None declared, Pavanish Kumar: None declared, Dianyan Guo: None declared, Ahmad Lajam: None declared, Warren Fong Consultant of: Abbvie, Janssen, Novartis, Speakers bureau: Abbvie, Janssen, Novartis, Ying Ying Leung Speakers bureau: Novartis, Janssen, Eli Lilly, Salvatore Albani: None declared