Secondary lymphoid tissue chemokine (CCL21) activates CXCR3 to trigger a Cl- current and chemotaxis in murine microglia.
Microglial cells represent the major immunocompetent element of the CNS and are activated by any type of brain injury or disease. A candidate for signaling neuronal injury to microglial cells is the CC chemokine ligand CCL21, given that damaged neurons express CCL21. Investigating microglia in acute slices and in culture, we demonstrate that a local application of CCL21 for 30 s triggered a Cl(-) conductance with lasted for tens of minutes. This response was sensitive to the Cl(-) channel blockers 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid and 4-acetamide-4'-isothiocyanatostilbene, 2,2'-disulfonic acid. Moreover, CCL21 triggered a chemotaxis response, which was sensitive to Cl(-) channel blockers. In microglial cells cultured from CCR7 knockout mice, CCL21 produced the same type of Cl(-) current as well as a chemotaxis response. In contrast, in microglial cells from CXCR3 knockout mice, CCL21 triggered neither a Cl(-) conductance nor a chemotaxis response after CCL21 application. We conclude that the CCL21-induced Cl(-) current is a prerequisite for the chemotaxis response mediated by the activation of CXCR3 but not CCR7 receptors, indicating that in brain CCL21 acts via a different receptor system than in lymphoid organs.
Rappert
Angelika
A
Max Delbrück Center for Molecular Medicine, Cellular Neuroscience, Berlin, Germany.
Biber
Knut
K
Nolte
Christiane
C
Lipp
Martin
M
Schubel
Andreas
A
Lu
Bao
B
Gerard
Norma P
NP
Gerard
Craig
C
Boddeke
Hendrikus W G M
HW
Kettenmann
Helmut
H
D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid / Q000494:pharmacology; D012856:4-Acetamido-4'-isothiocyanatostilbene-2,2'-disulfonic Acid / Q000494:pharmacology; D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D001921:Brain / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D001923:Brain Chemistry / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D054421:Chemokine CCL21; D054357:Chemokine CXCL10; D019742:Chemokines, CC / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D019743:Chemokines, CXC / Q000502:physiology; D002633:Chemotaxis / Q000187:drug effects / Q000502:physiology*; D018118:Chloride Channels / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology; D004553:Electric Conductivity; D066298:In Vitro Techniques; D007371:Interferon-gamma / Q000502:physiology; D008024:Ligands; D008262:Macrophage Activation / Q000187:drug effects / Q000502:physiology*; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D017628:Microglia / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D018408:Patch-Clamp Techniques; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine / Q000378:metabolism* / Q000502:physiology; D012694:Serine / Q000235:genetics
C515479:Ccl21c protein, mouse; D054421:Chemokine CCL21; D054357:Chemokine CXCL10; D019742:Chemokines, CC; D019743:Chemokines, CXC; D018118:Chloride Channels; C515188:Cxcr3 protein, mouse; D008024:Ligands; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine; D012856:4-Acetamido-4'-isothiocyanatostilbene-2,2'-disulfonic Acid; D012694:Serine; D007371:Interferon-gamma; D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid