scholarly journals Complement facilitates developmental microglial pruning of astrocyte and vascular networks

2022 ◽  
Author(s):  
Gopalan Gnanaguru ◽  
Steven J Tabor ◽  
Kentaro Yuda ◽  
Ryo Mukai ◽  
Jörg Köhl ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Immune Cell ◽  
Vascular Density ◽  
Vascular Networks ◽  
Vascular Patterning ◽  
Vascular Growth ◽  
Vascular Bed ◽  
Retinal Microglia ◽  
The Central Nervous System

Microglia, the resident immune cell of the central nervous system, play a pivotal role in facilitating neurovascular development through mechanisms that are not fully understood. This current work resolves a previously unknown role for microglia in facilitating the developmental pruning of the astrocytic template resulting in a spatially organized retinal vascular bed. Mechanistically, our study identified that local microglial expression of complement (C)3 and C3aR is necessary for the regulation of astrocyte patterning and vascular growth during retinal development. Ablation of retinal microglia, loss of C3 or C3aR reduced developmental pruning and clearance of astrocytic bodies leading to increased astrocyte density leading to altered vascular patterning during retinal vascular development. This data demonstrates that C3/C3aR signaling is an important checkpoint required for the finetuning of vascular density during neuroretinal development.

Retinal microglia polarization in diabetic retinopathy

2021 ◽  
Vol 38 ◽  
Author(s):  
Xin Li ◽  
Zi-Wei Yu ◽  
Hui-Yao Li ◽  
Yue Yuan ◽  
Xin-Yuan Gao ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Diabetic Retinopathy ◽  
Cytokine Production ◽  
Immune Cell ◽  
Microvascular Disease ◽  
Retinal Diseases ◽  
Microglia Polarization ◽  
Retinal Microglia ◽  
The Central Nervous System ◽  
Retinal Neurodegeneration

Abstract Microglia, the main immune cell of the central nervous system (CNS), categorized into M1-like phenotype and M2-like phenotype, play important roles in phagocytosis, cell migration, antigen presentation, and cytokine production. As a part of CNS, retinal microglial cells (RMC) play an important role in retinal diseases. Diabetic retinopathy (DR) is one of the most common complications of diabetes. Recent studies have demonstrated that DR is not only a microvascular disease but also retinal neurodegeneration. RMC was regarded as a central role in neurodegeneration and neuroinflammation. Therefore, in this review, we will discuss RMC polarization and its possible regulatory factors in early DR, which will provide new targets and insights for early intervention of DR.

scholarly journals Neurological and mental health consequences of COVID-19: potential implications for well-being and labor force

2021 ◽  
Author(s):  
I B Meier ◽  
C Vieira Ligo Teixeira ◽  
I Tarnanas ◽  
F Mirza ◽  
L Rajendran
Keyword(s):  
Mental Health ◽  
Central Nervous System ◽  
Nervous System ◽  
Cognitive Impairment ◽  
Immune Cell ◽  
Previous History ◽  
Well Being ◽  
Acute Disseminated Encephalomyelitis ◽  
The Central Nervous System ◽  
Neurological Protection

Abstract Recent case studies show that the SARS-CoV-2 infectious disease, COVID-19, is associated with accelerated decline of mental health, in particular, cognition in elderly individuals, but also with neurological and neuropsychiatric illness in young people. Recent studies also show a bidirectional link between COVID-19 and mental health in that people with previous history of psychiatric illness have a higher risk for contracting COVID-19 and that COVID-19 patients display a variety of psychiatric illnesses. Risk factors and the response of the central nervous system to the virus show large overlaps with pathophysiological processes associated with Alzheimer’s disease, delirium, post-operative cognitive dysfunction and acute disseminated encephalomyelitis, all characterized by cognitive impairment. These similarities lead to the hypothesis that the neurological symptoms could arise from neuroinflammation and immune cell dysfunction both in the periphery as well as in the central nervous system and the assumption that long-term consequences of COVID-19 may lead to cognitive impairment in the well-being of the patient and thus in today’s workforce, resulting in large loss of productivity. Therefore, particular attention should be paid to neurological protection during treatment and recovery of COVID-19, while cognitive consequences may require monitoring.

scholarly journals Molecular patterns from a human gut-derived Lactobacillus strain suppress pathogenic infiltration of leukocytes into the central nervous system

2020 ◽  
Vol 17 (1) ◽  
Author(s):  
John Michael S. Sanchez ◽  
Daniel J. Doty ◽  
Ana Beatriz DePaula-Silva ◽  
D. Garrett Brown ◽  
Rickesha Bell ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Gut Microbiota ◽  
Immune Cell ◽  
Cell Infiltration ◽  
Immune Cell Infiltration ◽  
Human Gut ◽  
Chemokine Production ◽  
The Central Nervous System ◽  
Molecular Patterns

Abstract Background Multiple sclerosis (MS) is an inflammatory demyelinating disease that affects 2.5 million people worldwide. Growing evidence suggests that perturbation of the gut microbiota, the dense collection of microorganisms that colonize the gastrointestinal tract, plays a functional role in MS. Indeed, specific gut-resident bacteria are altered in patients with MS compared to healthy individuals, and colonization of gnotobiotic mice with MS-associated microbiota exacerbates preclinical models of MS. However, defining the molecular mechanisms by which gut commensals can remotely affect the neuroinflammatory process remains a critical gap in the field. Methods We utilized monophasic experimental autoimmune encephalomyelitis (EAE) in C57BL/6J mice and relapse-remitting EAE in SJL/J mice to test the effects of the products from a human gut-derived commensal strain of Lactobacillus paracasei (Lb). Results We report that Lb can ameliorate preclinical murine models of MS with both prophylactic and therapeutic administrations. Lb ameliorates disease through a Toll-like receptor 2-dependent mechanism via its microbe-associated molecular patterns that can be detected in the systemic circulation, are sufficient to downregulate chemokine production, and can reduce immune cell infiltration into the central nervous system (CNS). In addition, alterations in the gut microbiota mediated by Lb-associated molecular patterns are sufficient to provide partial protection against neuroinflammatory diseases. Conclusions Local Lb modulation of the gut microbiota and the shedding of Lb-associated molecular patterns into the circulation may be important physiological signals to prevent aberrant peripheral immune cell infiltration into the CNS and have relevance to the development of new therapeutic strategies for MS.

Immune cell profiling in the cerebrospinal fluid of patients with primary angiitis of the central nervous system reflects the heterogeneity of the disease

2018 ◽  
Vol 321 ◽  
pp. 109-116 ◽  
Author(s):  
Daniel Strunk ◽  
Andreas Schulte-Mecklenbeck ◽  
Kristin S. Golombeck ◽  
Gerd Meyer zu Hörste ◽  
Nico Melzer ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Cerebrospinal Fluid ◽  
Nervous System ◽  
Immune Cell ◽  
Primary Angiitis ◽  
The Central Nervous System

scholarly journals The effect of clozapine and MIS416 on demyelination, remyelination and immunomodulation in the murine cuprizone model

2021 ◽  
Author(s):  
◽  
Nicola Templeton
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Growth Factors ◽  
Immune Cell ◽  
Protective Effects ◽  
Cell Infiltrate ◽  
Motor Impairments ◽  
Immune Cell Infiltrate ◽  
The Central Nervous System ◽  
Improved Performance

<p>Multiple Sclerosis (MS) is a disorder of the central nervous system that affects approximately 2.5 million people worldwide. Due to the heterogeneous nature of the disease, and the want of an identified cause, treatment of MS remains difficult. Treatments are available, however these are limited in efficacy and are not suitable for all forms of MS. Disease pathology is characterised by the formation of demyelinating lesions in the central nervous system (CNS) which lead to cognitive and motor impairments associated with the disease. These CNS lesions can be classified as those with immune cell involvement or those without immune cell infiltrate, which are more commonly seen in progressive forms of MS, and currently, there are no treatments available for progressive MS.  Due to the limited options available for treating progressive MS, this thesis aims to identify the therapeutic effect provided by the immunomodulatory compounds, MIS416 and clozapine, in a non-immune mediated model of MS, which is believed to more closely resemble progressive disease. Both of these compounds have been shown previously to reduce disease burden in an immune-driven animal model of MS. To investigate the effect of immune-modulating therapies on lesions without immune cell infiltrate, the cuprizone model of non-immune demyelination was used.  In summary, the work presented in this thesis found that treatment with MIS416 and clozapine led to improved performance on behavioural assays, although neither agent inhibited cuprizone-induced demyelination or enhanced remyelination. The cellular mechanism behind the observed behavioural improvement is yet to be confirmed. MIS416 was able to maintain its previously identified immunomodulatory properties when administered in this novel setting. Moreover, novel changes to serum growth factors were identified that could provide unexpected benefit to MS patients administered MIS416. In addition to reversing cuprizone-induced behavioural deficits, clozapine reduced LPS-driven inflammatory cytokine production by microglia, indicating that clozapine has the ability to directly reduce inflammation, which may benefit progressive MS patients.   Protective effects provided by either of these compounds could aid in the development of unique combination therapies to target both the inflammatory immune component and the cellular components seen at different stages of MS. MIS416 induced changes to serum cytokines and growth factors in the periphery could be harnessed to treat not just MS but other auto-immune diseases characterised by a similar cytokine profile.</p>

scholarly journals The effect of clozapine and MIS416 on demyelination, remyelination and immunomodulation in the murine cuprizone model

2021 ◽  
Author(s):  
◽  
Nicola Templeton
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Growth Factors ◽  
Immune Cell ◽  
Protective Effects ◽  
Cell Infiltrate ◽  
Motor Impairments ◽  
Immune Cell Infiltrate ◽  
The Central Nervous System ◽  
Improved Performance

<p>Multiple Sclerosis (MS) is a disorder of the central nervous system that affects approximately 2.5 million people worldwide. Due to the heterogeneous nature of the disease, and the want of an identified cause, treatment of MS remains difficult. Treatments are available, however these are limited in efficacy and are not suitable for all forms of MS. Disease pathology is characterised by the formation of demyelinating lesions in the central nervous system (CNS) which lead to cognitive and motor impairments associated with the disease. These CNS lesions can be classified as those with immune cell involvement or those without immune cell infiltrate, which are more commonly seen in progressive forms of MS, and currently, there are no treatments available for progressive MS.  Due to the limited options available for treating progressive MS, this thesis aims to identify the therapeutic effect provided by the immunomodulatory compounds, MIS416 and clozapine, in a non-immune mediated model of MS, which is believed to more closely resemble progressive disease. Both of these compounds have been shown previously to reduce disease burden in an immune-driven animal model of MS. To investigate the effect of immune-modulating therapies on lesions without immune cell infiltrate, the cuprizone model of non-immune demyelination was used.  In summary, the work presented in this thesis found that treatment with MIS416 and clozapine led to improved performance on behavioural assays, although neither agent inhibited cuprizone-induced demyelination or enhanced remyelination. The cellular mechanism behind the observed behavioural improvement is yet to be confirmed. MIS416 was able to maintain its previously identified immunomodulatory properties when administered in this novel setting. Moreover, novel changes to serum growth factors were identified that could provide unexpected benefit to MS patients administered MIS416. In addition to reversing cuprizone-induced behavioural deficits, clozapine reduced LPS-driven inflammatory cytokine production by microglia, indicating that clozapine has the ability to directly reduce inflammation, which may benefit progressive MS patients.   Protective effects provided by either of these compounds could aid in the development of unique combination therapies to target both the inflammatory immune component and the cellular components seen at different stages of MS. MIS416 induced changes to serum cytokines and growth factors in the periphery could be harnessed to treat not just MS but other auto-immune diseases characterised by a similar cytokine profile.</p>

scholarly journals Physiology of Microglia

2011 ◽  
Vol 91 (2) ◽  
pp. 461-553 ◽  
Author(s):  
Helmut Kettenmann ◽  
Uwe-Karsten Hanisch ◽  
Mami Noda ◽  
Alexei Verkhratsky
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Immune Cell ◽  
Brain Parenchyma ◽  
Microglial Cells ◽  
Activation Process ◽  
Normal Brain ◽  
The Central Nervous System ◽  
Cellular Compartments ◽  
The Brain

Microglial cells are the resident macrophages in the central nervous system. These cells of mesodermal/mesenchymal origin migrate into all regions of the central nervous system, disseminate through the brain parenchyma, and acquire a specific ramified morphological phenotype termed “resting microglia.” Recent studies indicate that even in the normal brain, microglia have highly motile processes by which they scan their territorial domains. By a large number of signaling pathways they can communicate with macroglial cells and neurons and with cells of the immune system. Likewise, microglial cells express receptors classically described for brain-specific communication such as neurotransmitter receptors and those first discovered as immune cell-specific such as for cytokines. Microglial cells are considered the most susceptible sensors of brain pathology. Upon any detection of signs for brain lesions or nervous system dysfunction, microglial cells undergo a complex, multistage activation process that converts them into the “activated microglial cell.” This cell form has the capacity to release a large number of substances that can act detrimental or beneficial for the surrounding cells. Activated microglial cells can migrate to the site of injury, proliferate, and phagocytose cells and cellular compartments.

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