Type I IFNs Are Required to Promote Central Nervous System Immune Surveillance through the Recruitment of Inflammatory Monocytes upon Systemic Inflammation

Ramos, Javier María Peralta; Bussi, Claudio; Gaviglio, Emilia A.; Arroyo, Daniela S.; Baez, Natalia Soledad; Rodríguez-Galán, María Cecilia; Iribarren, Pablo

doi:10.3389/fimmu.2017.01666

Cited by 13 publications

(13 citation statements)

References 57 publications

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“…Type I IFN produced during vaginal HSV-1 infection induces tissue resident macrophages and DCs to produce CCL2 to recruit and initial population of inflammatory monocytes, which then enact a positive feedback loops to produce more CCL2 to attract further inflammatory monocytes ( 35 ). A similar phenomenon has been observed during vaginal HSV-2 infection, influenza infection, and inflammatory monocyte recruitment to the brain during LPS-induced systemic inflammation ( 2 , 36 , 37 ), With influenza infection, absence of IFNAR resulted in differentiation of Ly6C intermediate expressing monocytes rather than Ly6C hi inflammatory monocytes, which additionally had a different phenotype ( 36 ). Further, Seo et al demonstrated that Ifnar −/− bone marrow had a significantly decreased differentiation of hematopoietic cells into inflammatory monocytes in the presence of influenza infection ( 38 ).…”

Section: Introductionsupporting

confidence: 67%

The Dual Nature of Type I and Type II Interferons

2018

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Type I and type II interferons (IFN) are central to both combating virus infection and modulating the antiviral immune response. Indeed, an absence of either the receptor for type I IFNs or IFN-y have resulted in increased susceptibility to virus infection, including increased virus replication and reduced survival. However, an emerging area of research has shown that there is a dual nature to these cytokines. Recent evidence has demonstrated that both type I and type II IFNs have immunoregulatory functions during infection and type II immune responses. In this review, we address the dual nature of type I and type II interferons and present evidence that both antiviral and immunomodulatory functions are critical during virus infection to not only limit virus replication and initiate an appropriate antiviral immune response, but to also negatively regulate this response to minimize tissue damage. Both the activating and negatively regulatory properties of type I and II IFNs work in concert with each other to create a balanced immune response that combats the infection while minimizing collateral damage.

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Section: Introductionsupporting

confidence: 67%

The Dual Nature of Type I and Type II Interferons

2018

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“…The recent discovery of a CNS dural lymphatic system that drains macromolecules from the CNS into cervical lymph nodes, further challenges the established basic assumptions of the CNS as an immune privileged site (5–7). Systemic injection of the endotoxin LPS has been widely used as an inflammatory model (8, 9). These peripherally applied stimuli lead to a cytokine-storm that signals to the brain, triggering an immune response.…”

Section: Introductionmentioning

confidence: 99%

Peripheral Inflammation Regulates CNS Immune Surveillance Through the Recruitment of Inflammatory Monocytes Upon Systemic α-Synuclein Administration

et al. 2019

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Innate immune activation and chronic neuroinflammation are characteristic features of many neurodegenerative diseases including Parkinson's disease (PD) and may contribute to the pathophysiology of the disease. The discovery of misfolded alpha-synuclein (αSYN) protein aggregates, which amplify in a “prion-like” fashion, has led us to consider that pathogenic αSYN might be hijacking the activation and mobilization mechanism of the peripheral immune system to reach and disseminate within the CNS. Furthermore, our lab and other groups have recently shown that αSYN can adopt distinct fibril conformations or “strains” with varying levels of pathogenic impact. Therefore, the aim of this study was to assess the impact of peripheral inflammation on αSYN spreading in order to better understand the participation of the immune system in the progression of PD. The results presented here show that intraperitoneal LPS injection prior to systemic intravenous recombinant administration of two different αSYN pathogenic strains (fibrils or ribbons) in wild type mice, induces an increase in brain resident microglia and promotes the recruitment of leukocytes toward the brain and the spinal cord. Our findings show for the first time that αSYN can be internalized by LPS-primed inflammatory monocytes, which in turn favors the dissemination from the periphery toward the brain and spinal cord. Further, we found a differential recruitment of CD4+ and CD8+ T cells after LPS priming and subsequent administration of the αSYN ribbons strain. Together, these data argue for a role of the peripheral immune system in αSYN pathology.

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“…Monocytes were used as a model to mimic HIV-induced activation that transpires in the periphery, wherein presence or internalization of HIV-1 in monocytes confers activation (CD14 + /CD16 + ) and subsequent trafficking of “Trojan horse” monocytes across and within the BBB [11, 12]. The method used to differentiate Mϕ (CD14 − /CD11b + ) has been validated by our group to ensure that these cells are no longer expressing monocyte marker CD14 and are mature Mϕ (CD11b expression) [13, 17–20]. Mϕ or monocytes were treated with various concentrations of drug prior to infection (HIV-1 baL ) and maintained for 3 days before quantification of HLA-DR, CD163 (Mϕ), or CD14/CD16 (monocytes; Miltenyi Biotec, San Diego, CA).…”

Section: Methodsmentioning

confidence: 99%

Baricitinib reverses HIV-associated neurocognitive disorders in a SCID mouse model and reservoir seeding in vitro

Gavegnano

Haile

Hurwitz

et al. 2019

J Neuroinflammation

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Background Since HIV-associated neurocognitive disorders (HANDs) occur in up to half of HIV-positive individuals, even with combined antiretroviral therapy (cART), adjunctive therapies are needed. Chronic CNS inflammation contributes to HAND and HIV encephalitis (HIVE). Baricitinib is a JAK 1/2 inhibitor approved in the USA, EU, and Japan for rheumatoid arthritis, demonstrating potent inhibition of IL-6, D-dimer, CRP, TNF-α, IFN-α/β, and other pro-inflammatory cytokines. Methods Our modified murine HAND model was used to evaluate the ability of baricitinib to cross the blood-brain barrier (BBB) and modulate monocyte/macrophage-driven HAND. Severity of HAND was measured by assessing cognitive performance of low- and high-dose baricitinib treated versus untreated HAND mice. The severity of brain neuroinflammation was evaluated in these mouse groups after flow cytometric analyses. We also assessed the ability of baricitinib to block events in myeloid and lymphoid cells in vitro that may undergird the persistence of HIV in the central nervous system (CNS) in primary human macrophages (Mϕ) and lymphocytes including HIV replication, HIV-induced activation, reservoir expansion, and reservoir maintenance. Results In vivo, both doses of 10 and 50 mg/kg qd baricitinib crossed the BBB and reversed behavioral abnormalities conferred by HIV infection. Moreover, baricitinib significantly reduced HIV-induced neuroinflammation marked by glial activation: activated microglia (MHCII+/CD45+) and astrogliosis (GFAP). Baricitinib also significantly reduced the percentage of p24+ human macrophages in mouse brains (p < 0.05 versus HAND mice; t test). In vitro, baricitinib significantly reduced markers of persistence, reservoir size, and reseeding in Mϕ. Conclusion These results show that blocking the JAK/STAT pathway reverses cognitive deficits and curtails inflammatory markers in HAND in mice. Our group recently reported safety and tolerability of ruxolitinib in HIV-infected individuals (Marconi et al., Safety, tolerability and immunologic activity of ruxolitinib added to suppressive ART, 2019), underscoring potential safety and utility of JAK inhibitors for additional human trials. The data reported herein coupled with our recent human trial with JAK inhibitors provide compelling preclinical data and impetus for considering a trial of baricitinib in HAND individuals treated with cART to reverse cognitive deficits and key events driving viral persistence.

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Type I IFNs Are Required to Promote Central Nervous System Immune Surveillance through the Recruitment of Inflammatory Monocytes upon Systemic Inflammation

Cited by 13 publications

References 57 publications

The Dual Nature of Type I and Type II Interferons

The Dual Nature of Type I and Type II Interferons

Peripheral Inflammation Regulates CNS Immune Surveillance Through the Recruitment of Inflammatory Monocytes Upon Systemic α-Synuclein Administration

Baricitinib reverses HIV-associated neurocognitive disorders in a SCID mouse model and reservoir seeding in vitro

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