Suppressed oligodendrocyte steroidogenesis in multiple sclerosis: Implications for regulation of neuroinflammation

Abstract

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS). Neurosteroids are reported to exert anti-inflammatory effects in several neurological disorders. We investigated the expression and actions of the neurosteroid, dehydroepiandrosterone (DHEA), and its more stable 3β-sulphated ester, DHEA-S, in MS and associated experimental models. CNS tissues from patients with MS and animals with experimental autoimmune encephalomyelitis (EAE) displayed reduced DHEA concentrations, accompanied by diminished expression of the DHEA-synthesizing enzyme CYP17A1 in oligodendrocytes (ODCs), in association with increased expression of inflammatory genes including interferon (IFN)-γ and interleukin (IL)-1β. CYP17A1 was expressed variably in different human neural cell types but IFN-γ exposure selectively reduced CYP17A1 detection in ODCs. DHEA-S treatment reduced IL-1β and -6 release from activated human myeloid cells with minimal effect on lymphocyte viability. Animals with EAE receiving DHEA-S treatment showed reduced Il1b and Ifng transcript levels in spinal cord compared to vehicle-treated animals with EAE. DHEA-S treatment also preserved myelin basic protein immunoreactivity and reduced axonal loss in animals with EAE, relative to vehicle-treated EAE animals. Neurobehavioral deficits were reduced in DHEA-S-treated EAE animals compared with vehicle-treated animals with EAE. Thus, CYP17A1 expression in ODCs and its product DHEA were downregulated in the CNS during inflammatory demyelination while DHEA-S provision suppressed neuroinflammation, demyelination, and axonal injury that was evident as improved neurobehavioral performance. These findings indicate that DHEA production is an immunoregulatory pathway within the CNS and its restoration represents a novel treatment approach for neuroinflammatory diseases.

Caspase-1 inhibition prevents glial inflammasome activation and pyroptosis in models of multiple sclerosis

“…Furthermore, it was imperative to establish whether the up-regulation of inflammasome genes observed in MS brains was recapitulated in the EAE model before considering CNS-targeted therapies to attenuate inflammasome activation. To address this issue, EAE was induced in C57/Bl6 mice using complete Freund's adjuvant (CFA)/MOG 35-55 with pertussis toxin, as previously reported by our group (46,47), and tissues were collected at days 8 (preonset), 10 (onset), 15 (moderate disease), and 20 (peak disease) postinduction (PI) ( Fig. 5 and SI Appendix, Figs.…”

“…Western Blot Analysis. Immunoblot analysis of cell lysates was performed as described previously (47,65). See SI Appendix for details.…”

Changes in neurosteroidogenesis during demyelination and remyelination in cuprizone‐treated mice

“…There is evidence in the literature to support changes of neurosteroids being involved in the pathophysiology of MS. Thus, the brain of MS patients and EAE animals displays reduced ALLO and dehydroepiandrosterone levels and diminished expression of their synthesising enzymes . Other studies have reported that progesterone and its reduced metabolites DHP and ALLO are altered in the cerebrospinal fluid and plasma of EAE rats and MS patients .…”

“…Other studies have reported that progesterone and its reduced metabolites DHP and ALLO are altered in the cerebrospinal fluid and plasma of EAE rats and MS patients . Interestingly, in EAE models, reduced levels of neurosteroids are frequently associated with inflammation and myelin loss, whereas exogenous administration of progesterone or synthetic progestins prevents demyelination, enhances myelin repair and reduces CNS inflammation . Furthermore, progesterone and the synthetic progestin Nestorone repair demyelinating lesions and increase oligodendrogenesis in the cuprizone model of MS …”

Human pegivirus‐1 associated leukoencephalitis: Clinical and molecular features

“…12 Slides were incubated with multiple antibodies, including rabbit anti-HPgV-1 NS5A (1:200) and anti-GFAP (glial fibrillary acidic protein), anti-CD3, anti-GST (glutathione S-transferase)-pi, or anti-Iba-1 (ionized calcium-binding adapter molecule 1) antibodies for immunofluorescent protein detection. 12 Slides were incubated with multiple antibodies, including rabbit anti-HPgV-1 NS5A (1:200) and anti-GFAP (glial fibrillary acidic protein), anti-CD3, anti-GST (glutathione S-transferase)-pi, or anti-Iba-1 (ionized calcium-binding adapter molecule 1) antibodies for immunofluorescent protein detection.…”