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Proinflammatory role of aquaporin‐4 in autoimmune neuroinflammation
Author(s) -
Li Lihua,
Zhang Hua,
Varrin-Doyer Michel,
Zamvil Scott S.,
Verkman A.S.
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.10-177279
Subject(s) - neuroinflammation , experimental autoimmune encephalomyelitis , myelin oligodendrocyte glycoprotein , astrocyte , proinflammatory cytokine , aquaporin 4 , immunology , microglia , immune system , biology , inflammation , central nervous system , endocrinology , biochemistry
Aquaporin‐4 (AQP4) deficiency in mice reduces neuroinflammation in experimental autoimmune encephalomyelitis (EAE) produced by active immunization with myelin oligodendrocyte glycoprotein peptide (MOG). Potential mechanisms for the protective effect of AQP4 deficiency were investigated, including AQP4‐dependent leukocyte and microglia cell function, immune cell entry in the central nervous system (CNS), intrinsic neuroinflammation, and humoral immune response. As we found with active‐immunization EAE, neuroinflammation was greatly reduced in AQP4‐knockout mice in adoptive‐transfer EAE. AQP4 was absent in immune cells, including activated T lymphocytes. The CNS migration of fluo‐rescently labeled, MOG‐sensitized T lymphocytes was comparable in wild‐type and AQP4‐knockout mice. Microglia did not express AQP4. Serum anti‐AQP4 antibodies were absent in EAE. Remarkably, intracerebral injection of LPS produced much greater neuroinflammation in wild‐type than in AQP4‐knockout mice, and cytokine (TNF‐α and IL‐6) secretion was reduced in astrocyte cultures from AQP4‐knockout mice. Ade‐novirus‐mediated expression of AQP4, or of an unrelated aquaporin, AQP1, increased cytokine secretion in astrocyte and nonastrocyte cell cultures, supporting the involvement of aquaporin water permeability in cyto‐kine secretion. Our data suggest an intrinsic proinflammatory role of AQP4 involving AQP4‐dependent astrocyte swelling and cytokine release. Reduction in AQP4 water transport may be protective in neuroinflammatory CNS diseases.—Li, L., Zhang, H., Varrin‐Doyer, M., Zamvil, S. S., Verkman, A. S. Proinflammatory role of aquaporin‐4 in autoimmune neuroinflammation. FASEB J. 25, 1556–1566 (2011). www.fasebj.org