1. Academic Validation
  2. A novel role of lactate: Promotion of Akt-dependent elongation of microglial process

A novel role of lactate: Promotion of Akt-dependent elongation of microglial process

  • Int Immunopharmacol. 2023 Apr 17;119:110136. doi: 10.1016/j.intimp.2023.110136.
Hongxiang Hong 1 Jianbin Su 2 Yi Zhang 3 Guanhua Xu 1 Chao Huang 4 Guofeng Bao 1 Zhiming Cui 5
Affiliations

Affiliations

  • 1 Department of Spine Surgery, The Second Affiliated Hospital of Nantong University, #6 North Road Hai'er Xiang, Nantong 226001, Jiangsu Province, China.
  • 2 Department of Endocrinology, The Second Affiliated Hospital of Nantong University, #6 North Road Hai'er Xiang, Nantong 226001, Jiangsu Province, China.
  • 3 Department of Pharmacy, The First People's Hospital of Yancheng, Yancheng First Hospital, Affiliated of Nanjing University Medical School, #66 Renmin South Road, Yancheng 224006, Jiangsu Province, China; Department of Pharmacology, School of Pharmacy, Nantong University, #19 Qixiu Road, Nantong 226001, Jiangsu Province, China.
  • 4 Department of Pharmacology, School of Pharmacy, Nantong University, #19 Qixiu Road, Nantong 226001, Jiangsu Province, China.
  • 5 Department of Spine Surgery, The Second Affiliated Hospital of Nantong University, #6 North Road Hai'er Xiang, Nantong 226001, Jiangsu Province, China. Electronic address: ntgkczmy@163.com.
Abstract

As a key component of the innate immune system, over-activation of microglia that occurs in nervous system diseases is usually accompanied by retraction of their branched processes. Reversal of microglial process retraction is a potential strategy to prevent neuroinflammation. In our previous studies, we reported some molecules that can promote the elongation of microglial processes under in vitro and in vivo conditions, such as butyrate, β-hydroxybutyrate, sulforaphane, diallyl disulfide, compound C, and KRIBB11. Here, we found that lactate, a molecule that mimics endogenous lactic acid and has been shown to suppress neuroinflammation, reversibly triggered significant elongations of processes in microglia under cultured and in vivo conditions. Pretreatment with lactate also prevented lipopolysaccharide (LPS)-induced shortening of microglial processes under cultured and in vivo conditions, pro-inflammatory responses in primary cultured microglia and prefrontal cortex, and depression-like behaviors in mice. Mechanistic studies revealed that incubation with lactate increased phospho-Akt levels in primary cultured microglia and inhibition of Akt blocked the pro-elongation effect of lactate on the microglial process under cultured and in vivo conditions, suggesting that the regulatory effect of lactate on the microglial process is dependent on activation of Akt. Inhibition of Akt also abolished the preventive effect of lactate on LPS-induced inflammatory responses in primary cultured microglia and prefrontal cortex and on LPS-induced depression-like behaviors in mice. Overall, these results demonstrate that lactate can induce Akt-mediated elongation of the microglial process, which appropriately contributes to the inhibition of microglia-mediated neuroinflammation.

Keywords

Akt; Lactate; Microglia; Neuroinflammation; Process elongation.

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