Georgetown University
Biology and Pathology

Author Of 1 Presentation

Invited Presentations Invited Abstracts

HT01.03 - Presentation 03

Speakers
Authors
Presentation Number
HT01.03
Presentation Topic
Invited Presentations
Lecture Time
09:39 - 09:51

Presenter Of 1 Presentation

Invited Presentations Invited Abstracts

HT01.03 - Presentation 03

Speakers
Authors
Presentation Number
HT01.03
Presentation Topic
Invited Presentations
Lecture Time
09:39 - 09:51

Invited Speaker Of 1 Presentation

Invited Presentations Invited Abstracts

HT01.03 - Presentation 03

Speakers
Authors
Presentation Number
HT01.03
Presentation Topic
Invited Presentations
Lecture Time
09:39 - 09:51

Author Of 1 Presentation

Neuroprotection, Regeneration and/or Remyelination Poster Presentation

P0774 - Bryostatin-1 modulates CNS innate immunity and augments remyelination (ID 1755)

Speakers
Presentation Number
P0774
Presentation Topic
Neuroprotection, Regeneration and/or Remyelination

Abstract

Background

Chronic, compartmentalized activation of central nervous system (CNS) innate immune cells drives progression and prevents remyelination in multiple sclerosis (MS), yet therapies targeting this aspect of inflammation do not exist. Bryostatin-1 (bryo-1) is a clinically safe, brain-penetrant macrocyclic lactone we previously found to have anti-inflammatory effects on peripheral myeloid cells, promoting a shift to tolerogenic/regulatory phenotypes and thereby attenuating rodent experimental autoimmune encephalomyelitis (EAE). The therapeutic target mediating this effect remains uncertain, and it is not known whether bryo-1 directly impacts CNS-resident (rather than peripheral) innate myeloid cells with downstream effects on myelin repair.

Objectives

1) To identify the mechanistic target of bryo-1 in innate myeloid cells; 2) To determine whether bryo-1 alters the phenotype of CNS-resident innate immune cells; 3) To evaluate the impact of immune modulation with bryo-1 on remyelination in lysolecithin-induced demyelination.

Methods

A combination of pharmacologic and genetic tools were used to determine the mechanistic target of bryo-1 mediating its effects in cultured macrophages and EAE. To determine whether bryo-1 acts directly on CNS-resident innate immune cells, we examined the effects of bryo-1 on microglia and astrocyte phenotype both in vitro and in two in vivo models – lysolecithin-induced demyelination and late-stage C57BL/6J EAE. Finally, we examined the effect of systemic treatment with bryo-1 on myelin repair following lysolecithin-induced demyelination.

Results

We found that the immunologic effects of bryo-1 are mediated by protein kinase C (PKC), both in vitro and in vivo. In cultured microglia and in vivo models, bryo-1 prevents pro-inflammatory activation and promotes homeostatic/regenerative phenotypic markers. Preliminary studies have shown that systemic treatment with bryo-1 augments re-population of oligodendrocyte-lineage cells and remyelination within demyelinated lesions.

Conclusions

PKC mediates the effects of bryo-1 on innate immune phenotype and represents a therapeutic target for future studies. Bryo-1 promotes a regenerative phenotype within CNS-resident microglia, both in vitro and in vivo, with preliminary data suggesting a potential downstream impact on myelin repair. Given its established safety profile in humans in trials of cancer and Alzheimer’s disease, bryo-1 holds promise as a modulator of compartmentalized inflammation in progressive MS.

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