PD-L1 (Programmed Death Ligand 1) Protects Against Experimental Intracerebral Hemorrhage–Induced Brain Injury

Han, Ranran; Luo, Jiaying; Shi, Yuhua; Yao, Yang; Hao, Junwei

doi:10.1161/strokeaha.117.016705

Cited by 57 publications

(36 citation statements)

References 35 publications

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“…Manipulation of PD-1:PD-L1/2 pathway is considered a potential therapeutic approach for treating autoimmune diseases ( 15 ). Impact of PD-L:PD-1 axis on differentiation of CD4 + T cell subsets has been reported in previous studies ( 32 , 56 , 57 ). In this study, we also observed that the increased expression of PD-1 in CD4 + T cells in T. spiralis -infected mice and knockout of PD-1 resulted in the recovery of inhibited CD4 + T cell proliferation caused by nematode infection, indicating PD-1 is involved in the nematode infection caused regulation of CD4 + T cells.…”

Section: Discussionsupporting

confidence: 75%

Trichinella spiralis Infection Mitigates Collagen-Induced Arthritis via Programmed Death 1-Mediated Immunomodulation

et al. 2018

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Helminth infection induces Th2-biased immune responses and inhibitory/regulatory pathways that minimize excessive inflammation to facilitate the chronic infection of helminth in the host and in the meantime, prevent host hypersensitivity from autoimmune or atopic diseases. However, the detailed molecular mechanisms behind modulation on inflammatory diseases are yet to be clarified. Programmed death 1 (PD-1) is one of the important inhibitory receptors involved in the balance of host immune responses during chronic infection. Here, we used the murine model to examine the role of PD-1 in CD4+ T cells in the effects of Trichinella spiralis infection on collagen-induced arthritis (CIA). Mice infected with T. spiralis demonstrated higher expression of PD-1 in the spleen CD4+ T cells than those without infection. Mice infected with T. spiralis 2 weeks prior to being immunized with type II collagen displayed lower arthritis incidence and significantly attenuated pathology of CIA compared with those of uninfected mice. The therapeutic effect of T. spiralis infection on CIA was reversed by blocking PD-1 with anti-PD-1 antibody, associated with enhanced Th1/Th17 pro-inflammatory responses and reduced Th2 responses. The role of PD-1 in regulating CD4+ T cell differentiation and proliferation during T. spiralis infection was further examined in PD-1 knockout (PD-1−/−) C57BL/6 J mice. Interestingly, T. spiralis-induced alteration of attenuated Th1 and enhanced Th2/regulatory T cell differentiation in wild-type (WT) mice was effectively diminished in PD-1−/− mice characterized by recovered Th1 cytokine levels, reduced levels of Th2 and regulatory cytokines and CD4+CD25+Foxp3+ cells. Moreover, T. spiralis-induced CD4+ T cell proliferation suppression in WT mice was partially restored in PD-1−/− mice. This study introduces the first evidence that PD-1 plays a critical role in helminth infection-attenuated CIA in a mouse model by regulating the CD4+ T cell function, which may provide the new insights into the mechanisms of helminth-induced immunomodulation of host autoimmunity.

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Section: Discussionsupporting

confidence: 75%

Trichinella spiralis Infection Mitigates Collagen-Induced Arthritis via Programmed Death 1-Mediated Immunomodulation

et al. 2018

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“…The overall pro-inflammatory cytokine production was decreased with down-regulation of IL-1β, IL-6, and TNF-α, and upregulation of IL-10. 126 As mentioned earlier, microglia polarization plays a very important role in ICH-induced secondary brain injury. In response to ICH, selective polarization to the pro-inflammatory type occurs.…”

Section: Programmed Death-1 Pathwaymentioning

confidence: 85%

“…125 PD-L1 administration significantly attenuated the severity of neurologic deficits, decreased cerebral edema by decreasing brain water content, and decreased hemorrhage volume. 126 PD-L1 also downsized the number of CD4 + T cells infiltrating the brain and overall percentages of Th1 and Th17 cells while increasing the overall percentages of the Th2 and regulatory T cells. The overall pro-inflammatory cytokine production was decreased with down-regulation of IL-1β, IL-6, and TNF-α, and upregulation of IL-10.…”

Section: Programmed Death-1 Pathwaymentioning

confidence: 92%

Neuroinflammation after Intracerebral Hemorrhage and Potential Therapeutic Targets

et al. 2020

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Spontaneous intracerebral hemorrhage (ICH) is a catastrophic illness causing significant morbidity and mortality. Despite advances in surgical technique addressing primary brain injury caused by ICH, little progress has been made treating the subsequent inflammatory cascade. Pre-clinical studies have made advancements identifying components of neuroinflammation, including microglia, astrocytes, and T lymphocytes. After cerebral insult, inflammation is initially driven by the M1 microglia, secreting cytokines (e.g., interleukin-1β [IL-1β] and tumor necrosis factor-α) that are involved in the breakdown of the extracellular matrix, cellular integrity, and the blood brain barrier. Additionally, inflammatory factors recruit and induce differentiation of A1 reactive astrocytes and T helper 1 (Th1) cells, which contribute to the secretion of inflammatory cytokines, augmenting M1 polarization and potentiating inflammation. Within 7 days of ICH ictus, the M1 phenotype coverts to a M2 phenotype, key for hematoma removal, tissue healing, and overall resolution of inflammation. The secretion of anti-inflammatory cytokines (e.g., IL-4, IL-10) can drive Th2 cell differentiation. M2 polarization is maintained by the secretion of additional anti-inflammatory cytokines by the Th2 cells, suppressing M1 and Th1 phenotypes. Elucidating the timing and trigger of the anti-inflammatory phenotype may be integral in improving clinical outcomes. A challenge in current translational research is the absence of an equivalent disease animal model mirroring the patient population and comorbid pathophysiologic state. We review existing data and describe potential therapeutic targets around which we are creating a bench to bedside translational research model that better reflects the pathophysiology of ICH patients.

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“…While these results suggested that Cx43KO astrocytes adopted a pro-inflammatory profile, most canonical panreactive astrocyte markers such as Lcn2 (Lipocalin-2), Vim (Vimentin) or Gfap were not upregulated in Cx43KO astrocytes [ 5 , 6 ]. In addition, several anti-inflammatory markers were upregulated, among which the complement decay-accelerating factor CD55 and the membrane receptor CD274 which inhibits T-cell proliferation by blocking cell cycle progression and cytokine production [ 25 ] ( Table 1 ). The Toll-like receptor Tlr4 was also downregulated in Cx43KO astrocytes ( Supplementary Table S2 ), thus possibly reducing astrocyte capacity to activate an innate immune response [ 26 ].…”

Section: Resultsmentioning

confidence: 99%

Connexin 43 Controls the Astrocyte Immunoregulatory Phenotype

et al. 2018

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Astrocytes are the most abundant glial cells of the central nervous system and have recently been recognized as crucial in the regulation of brain immunity. In most neuropathological conditions, astrocytes are prone to a radical phenotypical change called reactivity, which plays a key role in astrocyte contribution to neuroinflammation. However, how astrocytes regulate brain immunity in healthy conditions is an understudied question. One of the astroglial molecule involved in these regulations might be Connexin 43 (Cx43), a gap junction protein highly enriched in astrocyte perivascular endfeet-terminated processes forming the glia limitans. Indeed, Cx43 deletion in astrocytes (Cx43KO) promotes a continuous immune recruitment and an autoimmune response against an astrocyte protein, without inducing any brain lesion. To investigate the molecular basis of this unique immune response, we characterized the polysomal transcriptome of hippocampal astrocytes deleted for Cx43. Our results demonstrate that, in the absence of Cx43, astrocytes adopt an atypical reactive status with no change in most canonical astrogliosis markers, but with an upregulation of molecules promoting immune recruitment, complement activation as well as anti-inflammatory processes. Intriguingly, while several of these upregulated transcriptional events suggested an activation of the γ-interferon pathway, no increase in this cytokine or activation of related signaling pathways were found in Cx43KO. Finally, deletion of astroglial Cx43 was associated with the upregulation of several angiogenic factors, consistent with an increase in microvascular density in Cx43KO brains. Collectively, these results strongly suggest that Cx43 controls immunoregulatory and angiogenic properties of astrocytes.

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PD-L1 (Programmed Death Ligand 1) Protects Against Experimental Intracerebral Hemorrhage–Induced Brain Injury

Cited by 57 publications

References 35 publications

Trichinella spiralis Infection Mitigates Collagen-Induced Arthritis via Programmed Death 1-Mediated Immunomodulation

Trichinella spiralis Infection Mitigates Collagen-Induced Arthritis via Programmed Death 1-Mediated Immunomodulation

Neuroinflammation after Intracerebral Hemorrhage and Potential Therapeutic Targets

Connexin 43 Controls the Astrocyte Immunoregulatory Phenotype

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