Role of astrocyte senescence regulated by the non- canonical autophagy in the neuroinflammation associated to cerebral malaria

  • Brain Behav Immun. 2023 Dec 27:S0889-1591(23)00412-9. doi: 10.1016/j.bbi.2023.12.030.
Fatima Hellani  1 ,  Inès Leleu  1 ,  Nasreddine Saidi  1 ,  Nathalie Martin  2 ,  Cécile Lecoeur  1 ,  Elisabeth Werkmeister  3 ,  David Koffi  4 ,  François Trottein  1 ,  Hélène Yapo-Etté  5 ,  Bidyut Das  6 ,  Corinne Abbadie  2 ,  Sylviane Pied  7
Affiliations
  • 1. Univ. Lille, CNRS UMR 9017-INSERM U1019, Center for Infection and Immunity of Lille-CIIL, Institut Pasteur de Lille F-59019 Lille, France.
  • 2. Univ. Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, UMR9020-U1277 - CANTHER - Cancer Heterogeneity, Plasticity and Resistance to Therapies F-59000 Lille, France.
  • 3. Univ. Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, US 41 - UMS 2014 - PLBS F-59000 Lille, France.
  • 4. Parasitology and Mycology Department, Institut Pasteur de Côte d'Ivoire, Ivory Coast.
  • 5. Institute of Forensic Medicine-Faculty of Health, University Félix Houphouët-Boigny of Abidjan, Ivory Coast.
  • 6. SCB Medical College, Cuttack, Orissa, India.
  • 7. Univ. Lille, CNRS UMR 9017-INSERM U1019, Center for Infection and Immunity of Lille-CIIL, Institut Pasteur de Lille F-59019 Lille, France. Electronic address: [email protected].
PMID: 38157948 DOI: 10.1016/j.bbi.2023.12.030
Abstract

Background: Cerebral malaria (CM) is a fatal neuroinflammatory syndrome caused (in humans) by the protozoa Plasmodium (P.) falciparum. Glial cell activation is one of the mechanisms that contributes to neuroinflammation in CM.

Result: By studying a mouse model of CM (caused by P. berghei ANKA), we describe that the induction of Autophagy promoted p21-dependent senescence in astrocytes and that CXCL-10 was part of the senescence-associated secretory phenotype. Furthermore, p21 expression was observed in post-mortem brain and peripheral blood samples from patients with CM. Lastly, we found that the depletion of senescent astrocytes with senolytic drugs abrogated inflammation and protected mice from CM.

Conclusion: our data provide evidence for a novel mechanism through which astrocytes could be involved in the neuropathophysiology of CM. p21 gene expression in blood cell and an elevated plasma CXCL-10 concentration could be valuable biomarkers of CM in humans. In the end, we believe senolytic drugs shall open up new avenues to develop newer treatment options.

Keywords
Astrocyte; Cellular senescence; Cerebral malaria; Inflammation; P21; Senolytic drugs.
Products