[HTML][HTML] PIF* promotes brain re-myelination locally while regulating systemic inflammation-clinically relevant multiple sclerosis M. smegmatis model

G Migliara, M Mueller, A Piermattei, C Brodie… - Oncotarget, 2017 - ncbi.nlm.nih.gov
G Migliara, M Mueller, A Piermattei, C Brodie, MJ Paidas, ER Barnea, F Ria
Oncotarget, 2017ncbi.nlm.nih.gov
Neurologic disease diagnosis and treatment is challenging. Multiple Sclerosis (MS) is a
demyelinating autoimmune disease with few clinical forms and uncertain etiology. Current
studies suggest that it is likely caused by infection (s) triggering a systemic immune
response resulting in antigen/non-antigen-related autoimmune response in central nervous
system (CNS). New therapeutic approaches are needed. Secreted by viable embryos,
PreImplantation Factor (PIF) possesses a local and systemic immunity regulatory role …
Abstract
Neurologic disease diagnosis and treatment is challenging. Multiple Sclerosis (MS) is a demyelinating autoimmune disease with few clinical forms and uncertain etiology. Current studies suggest that it is likely caused by infection (s) triggering a systemic immune response resulting in antigen/non-antigen-related autoimmune response in central nervous system (CNS). New therapeutic approaches are needed. Secreted by viable embryos, PreImplantation Factor (PIF) possesses a local and systemic immunity regulatory role. Synthetic PIF (PIF) duplicates endogenous peptide's protective effect in pre-clinical autoimmune and transplantation models. PIF protects against brain hypoxia-ischemia by directly targeting microglia and neurons. In chronic experimental autoimmune encephalitis (EAE) model PIF reverses paralysis while promoting neural repair. Herein we report that PIF directly promotes brain re-myelination and reverses paralysis in relapsing remitting EAE MS model. PIF crosses the blood-brain barrier targeting microglia. Systemically, PIF decreases pro-inflammatory IL23/IL17 cytokines, while preserving CNS-specific T-cell repertoire. Global brain gene analysis revealed that PIF regulates critical Na+/K+/Ca++ ions, amino acid and glucose transport genes expression. Further, PIF modulates oxidative stress, DNA methylation, cell cycle regulation, and protein ubiquitination while regulating multiple genes. In cultured astrocytes, PIF promotes BDNF-myelin synthesis promoter and SLC2A1 (glucose transport) while reducing deleterious E2F5, and HSP90ab1 (oxidative stress) genes expression. In cultured microglia, PIF increases anti-inflammatory IL10 while reducing pro-inflammatory IFNγ expression. Collectively, PIF promotes brain re-myelination and neuroprotection in relapsing remitting EAE MS model. Coupled with ongoing, Fast-Track FDA approved clinical trial, NCT# 02239562 (immune disorder), current data supports PIF's translation for neurodegenerative disorders therapy.
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