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FASEB J ; 36(9): e22494, 2022 09.
Article in English | MEDLINE | ID: covidwho-1997082


In a rat middle cerebral artery occlusion (MACo) model of ischemic stroke, intracerebroventricular administration of human recombinant hepatocyte growth factor (HGF) mitigated motor impairment and cortical infarction. Recombinant HGF reduced MCAo-induced TNFα and IL1ß expression, and alleviated perilesional reactivation of microglia and astrocyte. All of the aforementioned beneficial effects of HGF were antagonized by an inhibitor to the type II transmembrane serine protease matriptase (MTP). MCAo upregulated MTP mRNA and protein in the lesioned cortex. MTP protein, not the mRNA, was increased further by recombinant HGF but reduced when MTP inhibitor (MTPi) was added to the treatment. Changes of the endogenous active HGF by MCAo, HGF or MTPi paralleled with the changes of MTP protein under the same conditions whilst neither HGF mRNA nor the total endogenous HGF protein were altered. These data showed that the therapeutic effects of HGF in stroke brain is attributed to its proteolytic activation and that MTP is a main protease of the event. MCAo enhanced MTP mRNA and thus protein expression; the initial use of the recombinant active HGF stabilized MCAo-induced MTP protein and subsequent activation of endogenous latent HGF which in turn stabilized further MTP protein. A reciprocal regulation between MTP and HGF appears to be present where MTP promotes HGF activation and the active HGF prevents MTP protein turnover. This study, for the first time, shows that MTP can participate in neural protection in stroke brain through activation of HGF. The cycles of HGF-MTP regulation achieved preservation of the neurological activity.

Hepatocyte Growth Factor , Stroke , Animals , Brain/metabolism , Hepatocyte Growth Factor/genetics , Hepatocyte Growth Factor/metabolism , Humans , Infarction, Middle Cerebral Artery/drug therapy , Infarction, Middle Cerebral Artery/metabolism , Neuroprotection , RNA, Messenger/metabolism , Rats , Serine Endopeptidases , Serine Proteases/metabolism , Stroke/metabolism
Biomolecules ; 12(5)2022 04 25.
Article in English | MEDLINE | ID: covidwho-1809689


Neurological symptoms are increasingly recognized in SARS-CoV-2 infected individuals. However, the neuropathogenesis remains unclear and it is not possible to define a specific damage pattern due to brain virus infection. In the present study, 33 cases of brain autopsies performed during the first (February-April 2020) and the second/third (November 2020-April 2021) pandemic waves are described. In all the cases, SARS-CoV-2 RNA was searched. Pathological findings are described and compared with those presently published.

COVID-19 , Adult , Autopsy , Brain , COVID-19/epidemiology , Humans , RNA, Viral , SARS-CoV-2
Brain Behav Immun ; 91: 740-755, 2021 01.
Article in English | MEDLINE | ID: covidwho-1064860


Central nervous system (CNS) innate immunity plays essential roles in infections, neurodegenerative diseases, and brain or spinal cord injuries. Astrocytes and microglia are the principal cells that mediate innate immunity in the CNS. Pattern recognition receptors (PRRs), expressed by astrocytes and microglia, sense pathogen-derived or endogenous ligands released by damaged cells and initiate the innate immune response. Toll-like receptors (TLRs) are a well-characterized family of PRRs. The contribution of microglial TLR signaling to CNS pathology has been extensively investigated. Even though astrocytes assume a wide variety of key functions, information about the role of astroglial TLRs in CNS disease and injuries is limited. Because astrocytes display heterogeneity and exhibit phenotypic plasticity depending on the effectors present in the local milieu, they can exert both detrimental and beneficial effects. TLRs are modulators of these paradoxical astroglial properties. The goal of the current review is to highlight the essential roles played by astroglial TLRs in CNS infections, injuries and diseases. We discuss the contribution of astroglial TLRs to host defense as well as the dissemination of viral and bacterial infections in the CNS. We examine the link between astroglial TLRs and the pathogenesis of neurodegenerative diseases and present evidence showing the pivotal influence of astroglial TLR signaling on sterile inflammation in CNS injury. Finally, we define the research questions and areas that warrant further investigations in the context of astrocytes, TLRs, and CNS dysfunction.

Astrocytes/metabolism , Neurodegenerative Diseases/physiopathology , Toll-Like Receptors/physiology , Animals , Astrocytes/physiology , Brain/metabolism , Central Nervous System/immunology , Central Nervous System/metabolism , Central Nervous System Diseases/immunology , Central Nervous System Infections/pathology , Encephalitis/immunology , Humans , Immunity, Innate/physiology , Microglia/metabolism , Neurodegenerative Diseases/metabolism , Neurons/metabolism , Receptors, Pattern Recognition/immunology , Signal Transduction , Spinal Cord/pathology , Spinal Cord Injuries/pathology , Toll-Like Receptors/metabolism