Dataset Information

Microglial Ramification, Surveillance, and Interleukin-1? Release Are Regulated by the Two-Pore Domain K⁺ Channel THIK-1.

ABSTRACT: Microglia exhibit two modes of motility: they constantly extend and retract their processes to survey the brain, but they also send out targeted processes to envelop sites of tissue damage. We now show that these motility modes differ mechanistically. We identify the two-pore domain channel THIK-1 as the main K⁺ channel expressed in microglia in situ. THIK-1 is tonically active, and its activity is potentiated by P2Y₁₂ receptors. Inhibiting THIK-1 function pharmacologically or by gene knockout depolarizes microglia, which decreases microglial ramification and thus reduces surveillance, whereas blocking P2Y₁₂ receptors does not affect membrane potential, ramification, or surveillance. In contrast, process outgrowth to damaged tissue requires P2Y₁₂ receptor activation but is unaffected by blocking THIK-1. Block of THIK-1 function also inhibits release of the pro-inflammatory cytokine interleukin-1? from activated microglia, consistent with K⁺ loss being needed for inflammasome assembly. Thus, microglial immune surveillance and cytokine release require THIK-1 channel activity.

SUBMITTER: Madry C

PROVIDER: S-EPMC5783715 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Publications

Microglial Ramification, Surveillance, and Interleukin-1β Release Are Regulated by the Two-Pore Domain K+ Channel THIK-1.

Madry Christian C Kyrargyri Vasiliki V Arancibia-Cárcamo I Lorena IL Jolivet Renaud R Kohsaka Shinichi S Bryan Robert M RM Attwell David D

Neuron 20171228 2

Microglia exhibit two modes of motility: they constantly extend and retract their processes to survey the brain, but they also send out targeted processes to envelop sites of tissue damage. We now show that these motility modes differ mechanistically. We identify the two-pore domain channel THIK-1 as the main K+ channel expressed in microglia in situ. THIK-1 is tonically active, and its activity is potentiated by P2Y12 receptors. Inhibiting THIK-1 function pharmacologically ...[more]

PMID: 29290552

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Project description:The morphology of microglial cells is often closely related to their functions. The mechanisms that regulate microglial ramification are not well understood. Here we reveal the biological mechanisms by which astrocytes regulate microglial ramification. Morphological variation in mouse microglial cultures was measured in terms of cell area as well as branch number and length. Effects on microglial ramification were analyzed after microinjecting the toxin L-alpha-aminoadipic acid (L-AAA) in the mouse cortex or hippocampus to ablate astrocytes, and after culturing microglia on their own in an astrocyte-conditioned medium (ACM) or together with astrocytes in coculture. TGF-? expression was determined by Western blotting, immunohistochemistry, and ELISA. The TGF-? signaling pathway was blocked by the TGF-? antibody to assess the role of TGF-? on microglial ramification. The results showed that microglia had more and longer branches and smaller cell bodies in brain areas where astrocytes were abundant. In the mouse cortex and hippocampus, ablation of astrocytes by L-AAA decreased number and length of microglial branches and increased the size of cell bodies. Similar results were obtained with isolated microglia in culture. However, isolated microglia were able to maintain their multibranched structure for a long time when cultured on astrocyte monolayers. Ameboid microglia isolated from P0 to P3 mice showed increased ramification when cultured in ACM or on astrocyte monolayers. Microglia cultured on astrocyte monolayers showed more complex branching structures than those cultured in ACM. Blocking astrocyte-derived TGF-? decreased microglial ramification. Astrocytes induced the formation of protuberances on branches of microglia by forming glial fibers that increased traction. These experiments in mice suggest that astrocytes promote microglial ramification by forming glial fibers to create traction and by secreting soluble factors into the surroundings. For example, astrocyte-secreted TGF-? promotes microglia to generate primitive branches, whose ramification is refined by glial fibers.

Dataset Information

Microglial Ramification, Surveillance, and Interleukin-1? Release Are Regulated by the Two-Pore Domain K⁺ Channel THIK-1.

Publications

Microglial Ramification, Surveillance, and Interleukin-1β Release Are Regulated by the Two-Pore Domain K<sup>+</sup> Channel THIK-1.

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Dataset Information

Microglial Ramification, Surveillance, and Interleukin-1? Release Are Regulated by the Two-Pore Domain K+ Channel THIK-1.

Publications

Microglial Ramification, Surveillance, and Interleukin-1β Release Are Regulated by the Two-Pore Domain K<sup>+</sup> Channel THIK-1.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Microglial Ramification, Surveillance, and Interleukin-1? Release Are Regulated by the Two-Pore Domain K⁺ Channel THIK-1.