Neuroinflammation in cryopyrin-associated periodic fever syndrome: Implications of the NLRP3 inflammasome in the central nervous system

• Applicant: Dr. Elisabeth Schuh
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Molecular Biology and Physiology of Neurons and Glial Cells
• Term: from 2019 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 421414975

• Final Report Year: 2023

Final Report Abstract

Missense mutations in the PLCg2 gene can cause autoinflammation, antibody deficiency and immune dysregulation (APLAID). In vivo studies in existing PLCg2 mouse models are limited by the fact that the inflammatory disease phenotype does not transfer to the C57BL/6 background. Therefore, it has been challenging to validate in vitro studies linking autoinflammation in APLAID to the NLRP3 inflammasome. By generating a new mouse model carrying a human APLAID mutation (S707Y) we circumvented this problem and found to our surprise that the inflammatory infiltrates in skin, lung and gut were only partially ameliorated after removing inflammasome function via the deletion of caspase-1. Also, deleting IL-6 and TNF did not fully prevent APLAID mutant mice from autoinflammation. Overall, these findings are in accordance with poor treatment response for APLAID patients following treatments that block IL-1 or TNF. Further cytokine analysis revealed increased G-CSF levels as the most distinct feature in APLAID mice and patients. Treatment with an anti-G-CSF antibody completely suppressed clinical symptoms in mice with established APLAID in vivo, while immunodeficiency in the blood remained unaltered. APLAID mice were also fully rescued following bone marrow transplantation from healthy donors, associated with normalized G-CSF levels. To date, monogenic autoinflammatory diseases have predominantly been associated with activation of the inflammasome, type I interferons, or the NF- kB driven cytokines TNF and IL-6. Therefore, APLAID may represent the first in a new category of G-CSF driven autoinflammatory disease, for which targeted therapy is now conceivable.

Publications

• The role of PLCγ2 in immunological disorders, cancer, and neurodegeneration. Journal of Biological Chemistry, 297(2), 100905.
  Jackson, Jacob T.; Mulazzani, Elisabeth; Nutt, Stephen L. & Masters, Seth L.
  
• G-CSF drives autoinflammation in APLAID. Nature Immunology, 24(5), 814-826.
  Mulazzani, Elisabeth; Kong, Klara; Aróstegui, Juan I.; Ng, Ashley P.; Ranathunga, Nishika; Abeysekera, Waruni; Garnham, Alexandra L.; Ng, Sze-Ling; Baker, Paul J.; Jackson, Jacob T.; Lich, John D.; Hibbs, Margaret L.; Wicks, Ian P.; Louis, Cynthia & Masters, Seth L.