Neutralizing peripheral circulating IL1β slows the progression of ALS in a lentivirus‐infected OPTN^E478G mouse model

Abstract

Background: Amyotrophic lateral sclerosis (ALS) is irreversible and fatal within 3-5 years, with limited options for treatment. It is imperative to develop a symptombased treatment that may increase the survival of ALS patients and improve their quality of life. Inflammation status, especially elevated interleukin 1β (IL1β), has been reported to play a critical role in ALS progression. Our study determined that neutralizing circulating IL1β slows down the progression of ALS in an ALS mouse model. Methods: The ALS mouse model was developed by microinjection of lentiviruscarrying OPTN E478G (optineurin, a mutation from ALS patients) into the intra-motor cortex of mice. Peripheral circulating IL1β was neutralized by injecting anti-IL1β antibody into the tail vein. Enzyme-linked immunosorbent assay (ELISA) and real-time polymerase chain reaction (RT-PCR) were carried out to determine the protein and gene expression levels of IL1β. TUNEL assay was used to assess the neural cell death. Immunofluorescent staining of MAP2 and CASP3 was accomplished to evaluate neuronal cell apoptosis. Glial fibrillary acidic protein staining was performed to analyze the number of astrocytes. Rotarod test, grip strength test, balance beam test, and footprint test were conducted to assess the locomotive function after anti-IL1β treatment. Results: The model revealed that neuroinflammation contributes to ALS progression. ALS mice exhibited elevated neuroinflammation and IL1β secretion. After anti-IL1β treatment, ALS mice revealed decreased neural cell death and astrogliosis and gained improved muscle strength and motor ability. Conclusions: Blocking IL1β is a promising strategy to slow down the progression of ALS.

Fundamental roles of the Optineurin gene in the molecular pathology of Amyotrophic Lateral Sclerosis

“…Unfortunately, there is currently little research into the treatment of ALS due to OPTN deficiency. One study found that neutralizing peripheral circulating IL1β could regulate neuroinflammation and improve motor function in OPTNE478G mouse model ( Hu et al, 2023 ). Another study also found that blocking RIPK1 may provide a treatment option for OPTN mutation-mediated ALS by inhibiting axonal degeneration caused by inflammation and necroptosis ( Ito et al, 2016 ).…”

L’optineurine et les dysfonctionnements mitochondriaux dans la neurodégénérescence

“…Elle perturbe également le recrutement de l'OPTN aux chaînes d'ubiquitine et inhibe la mitophagie[36]. D'un point de vue clinique, l'utilisation d'anti-IL-1b améliore la symptomatologie de souris transgénique OPTN-E478G[37]. L'expression chez la souris d'une mutation (OPTN-470T5 ), qui inhibe également la liaison aux ubiquitine, n'a pas permis d'observer de neurodégénerescence, que ce soit chez la souris jeune ou âgée[38].…”