Distinct Plasma Immune Profile in ALS Implicates sTNFR-II in pAMPK/Leptin Homeostasis.

Int J Mol Sci

CERVO Brain Research Centre, Department of Psychiatry and Neuroscience, Faculty of Medicine, Université Laval, Québec City, QC G1J 2G3, Canada.

Published: March 2023

AI Article Synopsis

  • Amyotrophic lateral sclerosis (ALS) is a variable disease with survival ranging from months to decades, potentially influenced by immune system dysfunction.
  • Researchers measured 62 immune/metabolic factors in the plasma of sporadic ALS patients, finding significant decreases in immune mediators like leptin, particularly in those with rapid disease progression.
  • A unique plasma immune profile linked to rapid ALS progression was identified, characterized by increased sTNF-RII and CCL16, and decreased leptin levels, suggesting targeting the sTNF-RII/AMPK/leptin pathway could help restore immune-metabolic balance in ALS patients.

Article Abstract

Amyotrophic lateral sclerosis (ALS) is a clinically highly heterogeneous disease with a survival rate ranging from months to decades. Evidence suggests that a systemic deregulation of immune response may play a role and affect disease progression. Here, we measured 62 different immune/metabolic mediators in plasma of sporadic ALS (sALS) patients. We show that, at the protein level, the majority of immune mediators including a metabolic sensor, leptin, were significantly decreased in the plasma of sALS patients and in two animal models of the disease. Next, we found that a subset of patients with rapidly progressing ALS develop a distinct plasma assess immune-metabolic molecular signature characterized by a differential increase in soluble tumor necrosis factor receptor II (sTNF-RII) and chemokine (C-C motif) ligand 16 (CCL16) and further decrease in the levels of leptin, mostly dysregulated in male patients. Consistent with in vivo findings, exposure of human adipocytes to sALS plasma and/or sTNF-RII alone, induced a significant deregulation in leptin production/homeostasis and was associated with a robust increase in AMP-activated protein kinase (AMPK) phosphorylation. Conversely, treatment with an AMPK inhibitor restored leptin production in human adipocytes. Together, this study provides evidence of a distinct plasma immune profile in sALS which affects adipocyte function and leptin signaling. Furthermore, our results suggest that targeting the sTNF-RII/AMPK/leptin pathway in adipocytes may help restore assess immune-metabolic homeostasis in ALS.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10049559PMC
http://dx.doi.org/10.3390/ijms24065065DOI Listing

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