Lu Ying, Gu Yishan, Chan Anthony S L, Yung Ying, Wong Yung H
Division of Life Science and the Biotechnology Research Institute, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China.
School of Public Health, Nantong University, Nantong City 226019, China.
Int J Mol Sci. 2024 Dec 5;25(23):13079. doi: 10.3390/ijms252313079.
Communications between different cell types within a tissue are often critical for the proper functioning of an organ. In the central nervous system, interactions among neurons and glial cells are known to modulate neurotransmission, energy metabolism, extracellular ion homeostasis, and neuroprotection. Here we showed that bradykinin, a proinflammatory neuropeptide, can be detected by astrocytes, resulting in the secretion of cytokines that act on neurons. In astrocytic cell lines and primary astrocytes, bradykinin and several other ligands acting on G-coupled receptors stimulated Ca mobilization, which subsequently led to the release of leukemia inhibitory factor (LIF) and interleukin-6 (IL-6). The bradykinin B receptor antagonist, HOE-140, effectively blocked the ability of bradykinin to mobilize Ca and stimulate mitogen-activated protein kinases (MAPKs) in astrocytes. Interestingly, incubation of neuronal cell lines and primary cortical neurons with conditioned media from bradykinin-treated astrocytes resulted in the activation of STAT3, a key component downstream of LIF and IL-6 receptors. LIF was apparently the major active factor in the conditioned media as the STAT3 response was almost completely neutralized by an anti-LIF antiserum. The presence of kininogen and kallikrein transcripts in neuronal cells but not in astrocytic cells indicates that neurons can produce bradykinin. Correspondingly, conditioned media from neuronal cells stimulated MAPKs in astrocytes in a HOE-140-sensitive manner. These studies demonstrate that paracrine signaling between neurons and astrocytes may involve ligands of G-coupled receptors and cytokines such as LIF.
组织内不同细胞类型之间的通讯对于器官的正常功能往往至关重要。在中枢神经系统中，已知神经元和神经胶质细胞之间的相互作用可调节神经传递、能量代谢、细胞外离子稳态和神经保护作用。在此我们发现，促炎神经肽缓激肽可被星形胶质细胞检测到，从而导致作用于神经元的细胞因子分泌。在星形胶质细胞系和原代星形胶质细胞中，缓激肽和其他几种作用于G偶联受体的配体刺激了钙离子动员，随后导致白血病抑制因子（LIF）和白细胞介素-6（IL-6）的释放。缓激肽B受体拮抗剂HOE-140有效阻断了缓激肽在星形胶质细胞中动员钙离子和刺激丝裂原活化蛋白激酶（MAPK）的能力。有趣的是，用缓激肽处理过的星形胶质细胞的条件培养基孵育神经元细胞系和原代皮质神经元，导致信号转导和转录激活因子3（STAT3）激活，STAT3是LIF和IL-6受体下游的关键成分。LIF显然是条件培养基中的主要活性因子，因为抗LIF抗血清几乎完全中和了STAT3反应。神经元细胞中存在激肽原和激肽释放酶转录本，而星形胶质细胞中不存在，这表明神经元可以产生缓激肽。相应地，神经元细胞的条件培养基以HOE-140敏感的方式刺激星形胶质细胞中的MAPK。这些研究表明，神经元和星形胶质细胞之间的旁分泌信号传导可能涉及G偶联受体的配体和诸如LIF的细胞因子。
