The choroid plexus links innate immunity to CSF dysregulation in hydrocephalus

Stephanie M. Robert, Benjamin C. Reeves, Emre Kiziltug, Phan Q. Duy, Jason K. Karimy, M. Shahid Mansuri, Arnaud Marlier, Garrett Allington, Ana B.W. Greenberg, Tyrone DeSpenza, Amrita K. Singh, Xue Zeng, Kedous Y. Mekbib, Adam J. Kundishora, Carol Nelson-Williams, Le Thi Hao, Jinwei Zhang, Tu Kiet T. Lam, Rashaun Wilson, William E. ButlerMichael L. Diluna, Philip Feinberg, Dorothy P. Schafer, Kiavash Movahedi, Allen Tannenbaum, Sunil Koundal, Xinan Chen, Helene Benveniste, David D. Limbrick, Steven J. Schiff, Bob S. Carter, Murat Gunel, J. Marc Simard, Richard P. Lifton, Seth L. Alper, Eric Delpire, Kristopher T. Kahle

Research output: Contribution to journalArticlepeer-review

19 Scopus citations


The choroid plexus (ChP) is the blood-cerebrospinal fluid (CSF) barrier and the primary source of CSF. Acquired hydrocephalus, caused by brain infection or hemorrhage, lacks drug treatments due to obscure pathobiology. Our integrated, multi-omic investigation of post-infectious hydrocephalus (PIH) and post-hemorrhagic hydrocephalus (PHH) models revealed that lipopolysaccharide and blood breakdown products trigger highly similar TLR4-dependent immune responses at the ChP-CSF interface. The resulting CSF “cytokine storm”, elicited from peripherally derived and border-associated ChP macrophages, causes increased CSF production from ChP epithelial cells via phospho-activation of the TNF-receptor-associated kinase SPAK, which serves as a regulatory scaffold of a multi-ion transporter protein complex. Genetic or pharmacological immunomodulation prevents PIH and PHH by antagonizing SPAK-dependent CSF hypersecretion. These results reveal the ChP as a dynamic, cellularly heterogeneous tissue with highly regulated immune-secretory capacity, expand our understanding of ChP immune-epithelial cell cross talk, and reframe PIH and PHH as related neuroimmune disorders vulnerable to small molecule pharmacotherapy.

Original languageEnglish
Pages (from-to)764-785.e21
Issue number4
StatePublished - Feb 16 2023


  • CSF
  • NKCC1
  • SPAK
  • blood-CSF barrier
  • cerebrospinal fluid
  • choroid plexus
  • hydrocephalus
  • neuro-inflammation


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