Secukinumab attenuates reactive astrogliosis via IL‐17RA/(C/EBPβ)/SIRT1 pathway in a rat model of germinal matrix hemorrhage

Abstract

Aims Reactive astrogliosis plays a critical role in neurological deficits after germinal matrix hemorrhage (GMH). It has been reported that interleukin‐17A and IL‐17A receptor IL‐17RA/(C/EBPβ)/SIRT1 signaling pathway enhances reactive astrogliosis after brain injuries. We evaluated the effects of secukinumab on reactive astrogliosis in a rat pup model of GMH. Methods A total of 146 Sprague Dawley P7 rat pups were used. GMH was induced by intraparenchymal injection of collagenase. Secukinumab was administered intranasally 1 hour post‐GMH. C/EBPβ CRISPR or SIRT1 antagonist EX527 was administrated intracerebroventricularly (icv) 48 hours and 1 hour before GMH induction, respectively. Neurobehavior, Western blot, histology, and immunohistochemistry were used to assess treatment regiments in the short term and long term. Results The endogenous IL‐17A, IL‐17RA, C/EBPβ, and GFAP and proliferation marker CyclinD1 were increased, while SIRT1 expression was decreased after GMH. Secukinumab treatment improved neurological deficits, reduced ventriculomegaly, and increased cortical thickness. Additionally, treatment increased SIRT1 expression and lowered proliferation proteins PCNA and CyclinD1 as well as GFAP expression. C/EBPβ CRISPR activation plasmid and EX527 reversed the antireactive astrogliosis effects of secukinumab. Conclusion Secukinumab attenuated reactive astrogliosis and reduced neurological deficits after GMH, partly by regulating IL‐17RA/(C/EBPβ)/SIRT1 pathways. Secukinumab may provide a promising therapeutic strategy for GMH patients.

Nicotinamide Mononucleotide Alleviates Hyperosmolarity-Induced IL-17a Secretion and Macrophage Activation in Corneal Epithelial Cells/Macrophage Co-Culture System

“…This finding was consistent with previous result based on animal experiments of allograft rejection, T cell-driven retinal disease and germinal matrix hemorrhage. [40][41][42] The mounting evidences on the relationship between SIRT1 and IL-17a in various biological progresses demonstrated that they could be a potential regulation mechanism in other disorders. There was one limitation should be discussed in this experiment.…”

Germinal Matrix-Intraventricular Hemorrhage of the Preterm Newborn and Preclinical Models: Inflammatory Considerations

“…Other studies have also reported the implication of IL-17A and IL-17AR in GM-IVH pathology due to their role in inflammation and BBB breakdown after stroke. IL-17A and IL-17AR levels are increased, contributing to endogenous reduction of silent information regulator 1 expression and increased cell proliferation markers after collagenase-induced GM-IVH in rats [138]. Similar outcomes have been observed after systemic glycerol administration to neonate rabbits, that show increased reactive microglia and increased levels of pro-inflammatory and chemotactic effector molecules, including IL-1β, IL-6 or TNF-α, IL-8 or MCP [30,63,108].…”

“…Short and long-term neuronal death is observed [32], and accumulation and upregulation of iron-handling proteins are also observed around the lesions [133]. However, the effects of the collagenase lesions are also detected in distant regions and cortical thinning [32,131,[136][137][138] as well as cortical tau hyperphosphorylation have been observed [32]. General affection of the brain is supported by the widespread presence of microhemorrhages in the cortex, hippocampus and striatum from P7-lesioned mice the long term (P70) [32] and white matter lesions and basal ganglia loss are also detected after collagenase lesions [131].…”

IL‐20R Activation via rIL‐19 Enhances Hematoma Resolution through the IL‐20R1/ERK/Nrf2 Pathway in an Experimental GMH Rat Pup Model

“…GMH is a one of the most devastating stroke subtypes for newborns, where the major neurological complications after hemorrhage are neuroinflammation, cerebral palsy, PHH, and motor and cognitive deficits [ 36 ]. Currently, GMH research has primarily focused on neuroinflammation [ 29 , 37 ], reactive astrogliosis [ 31 , 35 ], blood-brain barrier (BBB) destruction [ 38 , 39 ], and hematoma resolution [ 12 , 40 ] which has been closely associated with hematoma. In this study, our focus is on the blood clot which is primary causative factor in GMH-induced secondary brain injury.…”

“…To be better observed and measured, histological slices were stained by Nissl. Ventricular volume and cortical thickness were evaluated as previously described in [ 31 ]. The brains were embedded with Optimal Cutting Temperature (OCT, Fisher Scientific, Waltham, MA) and sectioned into 20 μ m thick slices (Leica Microsystems, LM3050S).…”