Activation of GPR35 protects against cerebral ischemia by recruiting monocyte-derived macrophages

  • Sci Rep. 2020 Jun 10;10(1):9400. doi: 10.1038/s41598-020-66417-8.
Ozayra Sharmin   #  1 ,  Ariful Haque Abir   #  1 ,  Abdullah Potol  1  2 ,  Mahabub Alam  1 ,  Jewel Banik  1  3 ,  A F M Towheedur Rahman  1  4 ,  Nuzhat Tarannum  1 ,  Rasiqh Wadud  1  5 ,  Zaki Farhad Habib  1  6 ,  Mahbubur Rahman  7
Affiliations
  • 1. Laboratory of Pharmacology, Department of Pharmaceutical Sciences, School of Health & Life Sciences, North South University, Bashundhra R/A, Dhaka, 1229, Bangladesh.
  • 2. Faculty of Medicine, Friedrich Schiller University Jena, 07743, Jena, Germany.
  • 3. Deptartment of Neurobiology & Developmental Sciences, College of Medicine, UAMS, 4301W. Markham St., Little Rock, AR, 72205, USA.
  • 4. Milwaukee Institute of Drug Discovery, Department of chemistry and Biochemistry, University of Wisconsin-Milwaukee, Milwaukee, WI, 53211, USA.
  • 5. Department of Veterinary Medicine, University of Cambridge, Madingley Road, Cambridge, CB3 0ES, UK.
  • 6. Department of Physiology, Development and Neuroscience, University of Cambridge, Downing Street, Cambridge, UK.
  • 7. Laboratory of Pharmacology, Department of Pharmaceutical Sciences, School of Health & Life Sciences, North South University, Bashundhra R/A, Dhaka, 1229, Bangladesh. [email protected].
  • # Contributed equally.
PMID: 32523084 DOI: 10.1038/s41598-020-66417-8
Abstract

Pamoic acid is a potent ligand for G protein Coupled Receptor 35 (GPR35) and exhibits antinociceptive property. GPR35 activation leads to increased energy utilization and the expression of anti-inflammatory genes. However, its role in brain disorders, especially in stroke, remains unexplored. Here we show in a mouse model of stroke that GPR35 activation by pamoic acid is neuroprotective. Pharmacological inhibition of GPR35 reveals that pamoic acid reduces infarcts size in a GPR35 dependent manner. The flowcytometric analysis shows the expression of GPR35 on the infiltrating monocytes/macrophages and neutrophils in the ischemic brain. Pamoic acid treatment results in a preferential increment of noninflammatory Ly-6CLo monocytes/macrophages in the ischemic brain along with the reduced neutrophil counts. The neuroprotective effect of GPR35 activation depends on protein kinase B (Akt) and p38 MAPK. Together we conclude that GPR35 activation by pamoic acid reprograms Ly-6CLo monocytes/macrophages to relay a neuroprotective signal into the ischemic brain.

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