Abstract
Regulation of microglial migration is not well understood. In this study, we proposed that Na+/H+ exchanger isoform 1 (NHE-1) is important in microglial migration. NHE-1 protein was co-localized with cytoskeletal protein ezrin in lamellipodia of microglia and maintained its more alkaline intracellular pH (pHi). Chemoattractant bradykinin (BK) stimulated microglial migration by increasing lamellipodial area and protrusion rate, but reducing lamellipodial persistence time. Interestingly, blocking NHE-1 activity with its potent inhibitor HOE 642 not only acidified microglia, abolished the BK-triggered dynamic changes of lamellipodia, but also reduced microglial motility and microchemotaxis in response to BK. In addition, NHE-1 activation resulted in intracellular Na+ loading as well as intracellular Ca2+ elevation mediated by stimulating reverse mode operation of Na+/Ca2+ exchange (NCXrev). Taken together, our study shows that NHE-1 protein is abundantly expressed in microglial lamellipodia and maintains alkaline pHi in response to BK stimulation. In addition, NHE-1 and NCXrev play a concerted role in BK-induced microglial migration via Na+ and Ca2+ signaling.
Highlights
Microglia are resident macrophages and ubiquitously distributed in the central nervous system (CNS)
Our study clearly demonstrated that Na+/H+ exchanger isoform 1 (NHE-1) protein is co-localized with cytoskeletal protein ezrin in microglial lamellipodia and stimulates microglial migration by regulating alkaline pHi and Na+ and Ca2+ signaling
When NHE-1 activity was blocked with HOE 642, actin intensity in the lamellipodial area returned to the control level (95.4 ± 0.5% of control, n = 4)
Summary
Microglia are resident macrophages and ubiquitously distributed in the central nervous system (CNS). They serve as sensors for CNS homeostasis disruption and can be activated under various pathological conditions [1]. One of the earliest microglial responses to brain injury is its migration to the site of injury or inflammation [2]. Extracellular ATP and ADP released from ischemic and traumatic brain tissues can stimulate microglial migration [3]. Injury to the CNS tissues releases other chemotactic factors including morphine [4], epidermal growth factor [5], cannabinoids [6] and bradykinin [7], which stimulate microglial migration to the site of injury. Microglia have been demonstrated to move along the chemokine gradients in in vitro and in vivo injury models for experimental autoimmune encephalitis, Alzheimer’s disease, or cerebral ischemia [8]
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