Etiogenic factors present in the cerebrospinal fluid from amyotrophic lateral sclerosis patients induce predominantly pro-inflammatory responses in microglia

Pooja-Shree Mishra, K. Vijayalakshmi, A. Nalini, T. N. Sathyaprabha, B. W. Kramer, Phalguni Anand Alladi, T. R. Raju*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

28 Citations (Web of Science)

Abstract

Background: Microglial cell-associated neuroinflammation is considered as a potential contributor to the pathophysiology of sporadic amyotrophic lateral sclerosis. However, the specific role of microglia in the disease pathogenesis remains to be elucidated. Methods: We studied the activation profiles of the microglial cultures exposed to the cerebrospinal fluid from these patients which recapitulates the neurodegeneration seen in sporadic amyotrophic lateral sclerosis. This was done by investigating the morphological and functional changes including the expression levels of prostaglandin E2 (PGE2), cyclooxygenase-2 (COX-2), TNF-alpha, IL-6, IFN-gamma, IL-10, inducible nitric oxide synthase (iNOS), arginase, and trophic factors. We also studied the effect of chitotriosidase, the inflammatory protein found upregulated in the cerebrospinal fluid from amyotrophic lateral sclerosis patients, on these cultures. Results: We report that the cerebrospinal fluid from amyotrophic lateral sclerosis patients could induce an early and potent response in the form of microglial activation, skewed primarily towards a pro-inflammatory profile. It was seen in the form of upregulation of the pro-inflammatory cytokines and factors including IL-6, TNF-alpha, iNOS, COX-2, and PGE2. Concomitantly, a downregulation of beneficial trophic factors and anti-inflammatory markers Including VEGF, glial cell line-derived neurotrophic factor, and IFN-gamma was seen. In addition, chitotriosidase-1 appeared to act specifically via the microglial cells. Conclusion: Our findings demonstrate that the cerebrospinal fluid from amyotrophic lateral sclerosis patients holds enough cues to induce microglial inflammatory processes as an early event, which may contribute to the neurodegeneration seen in the sporadic amyotrophic lateral sclerosis. These findings highlight the dynamic role of microglial cells in the pathogenesis of the disease, thus suggesting the need for a multidimensional and temporally guarded therapeutic approach targeting the inflammatory/ pathways for its treatment.

Original languageEnglish
Article number251
Number of pages18
JournalJournal of Neuroinflammation
Volume14
DOIs
Publication statusPublished - 16 Dec 2017

Keywords

  • Sporadic ALS
  • Microglia
  • ALS-CSF
  • Neuroinflammation
  • Non-cell autonomous pathology
  • Chitotriosidase
  • IL-6
  • IL-10
  • TNF-alpha
  • IFN-gamma
  • PGE2
  • COX-2
  • iNOS
  • Arginase
  • VEGF
  • GDNF
  • NF-KAPPA-B
  • MOUSE MODEL
  • GLUTAMATE RELEASE
  • GENE-EXPRESSION
  • SUPEROXIDE-DISMUTASE
  • ALZHEIMERS-DISEASE
  • SPINAL-CORDS
  • MUTANT SOD1
  • CELL-LINE
  • IN-VITRO

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