PIF* promotes brain re-myelination locally while regulating systemic inflammation- clinically relevant multiple sclerosis M.smegmatis model
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Giuseppe Migliara1,7,*, Martin Mueller2,3,*, Alessia Piermattei1, Chaya Brodie4, Michael J. Paidas3, Eytan R. Barnea5,6,*, Francesco Ria1,*
1Università Cattolica del S. Cuore, Institute of General Pathology, Largo Francesco Vito, 100168 Rome, Italy
2Department of Obstetrics and Gynecology, University of Bern, 3010, Bern, Switzerland
3Department of Obstetrics, Gynecology and Reproductive Sciences, Yale Women and Children’s Center for Blood Disorders and Preeclampsia Advancement, Yale University School of Medicine, FMB 3398, New Haven, CT 06520-8063, USA
4Department of Neurosurgery, Henry Ford Hospital, Detroit, MI 48202, USA
5Society for the Investigation of Early Pregnancy (SIEP), Cherry Hill, NJ 08003, USA
6BioIncept, Cherry Hill, NJ 08003, USA
7Present address: Department of Public Health and Infectious Diseases, Sapienza University of Rome, 00185 Rome, Italy
*GM and MM and ERB and FR contributed equally, PIF* PROPRIETARY
Eytan R. Barnea, email: [email protected]
Keywords: preImplantation factor, neuroprotection, neuroregeneration, M. smegmatis bacteria, RR-EAE clinically-relevant model
Received: July 14, 2016 Accepted: January 10, 2017 Published: February 24, 2017
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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