Bradykinin-Induced Microglial Migration Mediated by B₁-Bradykinin Receptors Depends on Ca²⁺Influx via Reverse-Mode Activity of the Na⁺/Ca²⁺Exchanger

Abstract

Bradykinin (BK) is produced and acts at the site of injury and inflammation. In the CNS, migration of microglia toward the lesion site plays an important role pathologically. In the present study, we investigated the effect of BK on microglial migration. Increased motility of cultured microglia was mimicked by B 1 receptor agonists and markedly inhibited by a B 1 antagonist , but not by a B 2 receptor antagonist. BK induced chemotaxis in microglia isolated from wild-type and B 2 -knock-out mice but not from B 1 -knock-out mice. BK-induced motility was not blocked by pertussis toxin but was blocked by chelating intracellular Ca 2ϩ or by low extracellular Ca 2ϩ , implying that Ca 2ϩ influx is prerequisite. Blocking the reverse mode of Na ϩ /Ca 2ϩ exchanger (NCX) completely inhibited BK-induced migration. The involvement of NCX was further confirmed by using NCX ϩ/Ϫ mice; B 1 -agonist-induced motility and chemotaxis was decreased compared with that in NCX ϩ/ϩ mice. Activation of NCX seemed to be dependent on protein kinase C and phosphoinositide 3-kinase, and resultant activation of intermediate-conductance (IK-type) Ca 2ϩ -dependent K ϩ currents (I K(Ca) ) was activated. Despite these effects, BK did not activate microglia, as judged from OX6 staining. Using in vivo lesion models and pharmacological injection to the brain, it was shown that microglial accumulation around the lesion was also dependent on B 1 receptors and I K(Ca) . These observations support the view that BK functions as a chemoattractant by using the distinct signal pathways in the brain and, thus, attracts microglia to the lesion site in vivo.

Glioblastoma‐mesenchymal stem cell communication modulates expression patterns of kinin receptors: Possible involvement of bradykinin in information flow

“…These effects were most likely mediated by activation of phosphatidylinositol 3 kinase (PI3) Akt and extracellular signal-regulated kinases (ERK) pathways (29). Kinin receptormodulated proliferation was also observed for microglial cells (30) as well as for bladder carcinoma (14) and other cancers (25).…”

Kinins and microglial responses in bipolar disorder: a neuroinflammation hypothesis

“…Acting as chemoattractant at sites of injury, B1BKR agonists promote microglial migration through B1BKR activation in a G-protein independent pathway (Ifuku et al, 2007) and mediated by Ca 2+ -activated K + channel stimulation. Microglia migration was drastically reduced by the use of an antagonist of the B1BKR, but not for the B2BKR, indicating that microglia motility is B1BKR-dependent (Ifuku et al, 2007;Huisman et al, 2008). These findings were further investigated and corroborated in vivo.…”

New topics in bradykinin research

“…Following brain trauma, ko-B 1 animals showed lower lesion volume, while ko-B 2 animals showed less contusion, brain infarction and oedema, compared with wt animals (33, 34); bradykinin receptor ablation would therefore appear neuroprotective. Moreover, fewer microglial cells were detected in brain lesions of ko-B 1 mice compared with wt, suggesting bradykinin may influence neurological pathology via microglial migration; however, whether microglia are neuroprotective or neurodestructive appears to depend on the overall pathological milieu (35,36). Thus, depending on the pathological condition, bradykinin B 1 and B 2 receptor activity can confer either a protective or an aggravating effect and thus represent potential pharmacotherapeutic targets.…”