MMP9/RAGE pathway overactivation mediates redox dysregulation and neuroinflammation, leading to inhibitory/excitatory imbalance: a reverse translation study in schizophrenia patients.

Various mechanisms involved in schizophrenia pathophysiology, such as dopamine dysregulation, glutamate/NMDA receptor dysfunction, neuroinflammation or redox imbalance, all appear to converge towards an oxidative stress "hub" affecting parvalbumine interneurones (PVI) and their perineuronal nets (PNN) (Lancet Psychiatry. 2015;2:258-70); (Nat Rev Neurosci. 2016;17:125-34). We aim to investigate underlying mechanisms linking oxidative stress with neuroinflammatory and their long-lasting harmful consequences. In a transgenic mouse of redox dysregulation carrying a permanent deficit of glutathione synthesis (gclm-/-), the anterior cingulate cortex presented early in the development increased oxidative stress which was prevented by the antioxidant N-acetylcysteine (Eur J Neurosci. 2000;12:3721-8). This oxidative stress induced microglia activation and redox-sensitive matrix metalloproteinase 9 (MMP9) stimulation, leading to the receptor for advanced glycation end-products (RAGE) shedding into soluble and nuclear forms, and subsequently to nuclear factor-kB (NF-kB) activation and secretion of various cytokines. Blocking MMP9 activation prevented this sequence of alterations and rescued the normal maturation of PVI/PNN, even if performed after an additional insult that exacerbated the long term PVI/PNN impairments. MMP9 inhibition thus appears to be able to interrupt the vicious circle that maintains the long-lasting deleterious effects of the reciprocal interaction between oxidative stress and neuroinflammation, impacting on PVI/PNN integrity. Translation of these experimental findings to first episode patients revealed an increase in plasma soluble RAGE relative to healthy controls. This increase was associated with low prefrontal GABA levels, potentially predicting a central inhibitory/excitatory imbalance linked to RAGE shedding. This study paves the way for mechanistically related biomarkers needed for early intervention and MMP9/RAGE pathway modulation may lead to promising drug targets.

Correction: MMP9/RAGE pathway overactivation mediates redox dysregulation and neuroinflammation, leading to inhibitory/excitatory imbalance: a reverse translation study in schizophrenia patients.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Start of the Season in a Seasonal Work Context: A Better Understanding of the Difficulties Experienced by Seasonal Workers in the Food Processing Industry for the Prevention of Work-Related Musculoskeletal Disorders.

The specific period of the start of a new working season and a return to work after the off-season seems to be a critical moment for the musculoskeletal health of seasonal workers. This study aims to identify the difficulties and working conditions encountered by seasonal workers in this particular period of the working season which may increase the risk of work-related musculoskeletal disorders (WMSDs). An in-depth ergonomic work activity study, combined with a multiple case study of eight seasonal workers from a meat processing facility, was conducted. Various interviews (n = 24) and observations of work activity, organization, and production (n = 96 h) were held at different moments (off-season, return to work at the start of the season, and during the season). Critical work situations exposing workers to WMSD risks emerged and highlighted a diversity of difficulties, such as accomplishing work activity involving strong physical strain and a significant and underestimated mental load, and having to rapidly develop new skills or re-learn working strategies after a long off-period. The study findings have implications for developing actions to prevent WMSDs that target working conditions and support a return to work for returning seasonal workers and a start of work for new seasonal workers, and to address work disability in this context.