Macrophages mediate crucial innate immune responses via caspase-1-dependent processing and secretion of IL-1β and IL-18. While wild type Salmonella typhimurium infection is lethal to mice, a strain that persistently expresses flagellin was cleared by the cytosolic flagellin detection pathway via NLRC4 activation of caspase-1; however, this clearance was independent of IL-1β and IL-18. Instead, caspase-1 induced pyroptotic cell death released bacteria from macrophages, exposing them to uptake and killing by reactive oxygen species in neutrophils. Similarly, caspase-1 cleared Legionella and Burkholderia by cytokine independent mechanisms. Our results show, for the first time, that caspase-1 can clear intracellular bacteria in vivo independent of IL-1β and IL-18, and establish pyroptosis as an efficient mechanism of bacterial clearance by the innate immune system.

Caspase-1-induced pyroptosis is an innate immune effector mechanism against intracellular bacteria (111.33)

Intracerebral haemorrhage is inadequately controlled by current treatments, requiring new solutions to improve the prognosis. Following the primary injury, a proinflammatory cascade in the perihaematomal region, composed of activated resident microglia and astrocytes and infiltrated leucocytes, propagates neural cell death. The protracted nature of neuroinflammation in intracerebral haemorrhage provides a window of opportunity for therapies to subdue the undesired consequences. In animal models and early clinical trials in intracerebral haemorrhage, several drugs have reduced detrimental neuroinflammation without substantial compromise of the beneficial reparative aspects of an inflammatory response. Potential strategies include controlling excessive harmful neuroinflammation with minocycline, sphingosine-1-phosphate receptor modulators, and statins after a brain haemorrhage. The quick initiation of these drugs, particularly in high systemic doses, could be key to counteracting the evolving secondary injury in people with intracerebral haemorrhage and provides a promising way in which the poor prognosis of intracerebral haemorrhage might one day be counteracted.

Neuroinflammation in intracerebral haemorrhage: immunotherapies with potential for translation.

Intracerebral hemorrhage (ICH) is a subtype of stroke with high mortality and disability but no specific or effective treatment. In the last two decades, much has been learned about the pathologic ...

Potential therapeutic targets for intracerebral hemorrhage-associated inflammation: An update

Intracerebral hemorrhage (ICH) is a subtype of hemorrhagic stroke with high mortality and morbidity. The resulting hematoma within brain parenchyma induces a series of adverse events causing primary and secondary brain injury. The mechanism of injury after ICH is very complicated and has not yet been illuminated. This review discusses some key pathophysiology mechanisms in ICH such as oxidative stress (OS), inflammation, iron toxicity, and thrombin formation. The corresponding therapeutic targets and therapeutic strategies are also reviewed.

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Pathophysiological Mechanisms and Potential Therapeutic Targets in Intracerebral Hemorrhage.

Intracerebral hemorrhage (ICH) is a life-threatening subtype of cerebral stroke with high morbidity and mortality; however, effective treatment for ICH is still lacking. Adiponectin (APN) is a a kind of fat-derived plasma protein with beneficial effects in cerebrovascular disorders. In this study, we aimed to investigate the protective effects of recombinant APN peptide (APNp) on brain injury after ICH in adult male C57BL/6J mice and further explored the underlying molecular mechanisms of these effects. APNp treatment exerted dose-dependent neuroprotective effects including improved neurological function, decreased brain edema, reduced neural apoptosis, and alleviated blood-brain barrier (BBB) disruption in ICH mice. We found the massive accumulation of APNp on reactive astrocytes around brain microvessels under hemorrhage conditions by immunofluorescence analysis. mRNA sequencing (mRNA-seq) and transcriptome analysis indicated that APNp significantly attenuated the inflammatory response and mitochondrial respiratory dysfunction in astrocytes. Further study revealed that this process was, at least in part, reliant on the inhibition of Drp1-mediated excessive mitochondrial fission. More specifically, APNp increased AMP-activated protein kinase (AMPK) activation-dependent Drp1 serine 637 (S637) phosphorylation, which inhibited the translocation of Drp1 to the mitochondrial membrane and reduced mitochondrial fragmentation and the production of mitochondrial superoxide, ultimately attenuating inflammatory brain injury induced by hemorrhage. In conclusion, we propose APNp as a potential therapeutic agent for ICH. We provide the first mechanistic evidence that APNp can modulate Drp1-mediated mitochondrial fission, which then contributes to alleviating astrocyte-derived inflammation.

https://link.springer.com/content/pdf/10.1007/s12975-019-00768-x.pdf

Recombinant Adiponectin Peptide Ameliorates Brain Injury Following Intracerebral Hemorrhage by Suppressing Astrocyte-Derived Inflammation via the Inhibition of Drp1-Mediated Mitochondrial Fission.

Zhiqiang Wang

Papers

Role and mechanisms of cytokines in the secondary brain injury after intracerebral hemorrhage.