Fig. 2
Summary of the neuroimmune interaction mediated via CXCL13–CXCR5 signaling in the nervous system during chronic pain and neurological diseases. In the periphery (joint), during RA, CXCL13 activates ERK and p38 MAPK via CXCR5 to promote TNF production in MH7A cells, which may contribute to joint inflammation and pain in RA [89]. In dorsal root ganglia (DRG) and TG, during chronic pain, CXCL13 is produced from sensory neurons and activates CXCR5 expressed by sensory neurons via an autocrine manner [36, 37]. CXCR5 activation promotes TNF and IL-1β production in sensory neurons and enhances Nav1.8 channel activity via p38 MAPK to promote nociceptive neuron hyperexcitability [36, 37]. In SCDH, during chronic pain, CXCL13 is produced from spinal neurons. On one hand, CXCL13 acts on CXCR5 expressed by astrocytes to promote astrocyte activation, resulting in proinflammatory cytokine production, such as CCL2 and CCL7 [35]. On the other hand, CXCL13 activates CXCR5 expressed by neurons via an autocrine manner to promote IL-6 production [34]. These cytokines either directly activate spinal neurons or cause microglial activation to augment and maintain chronic pain condition. Conversely, in spinal cord ventral horn (SCVH), CXCL13 is produced from spinal motor neurons and acts on CXCR5 expressed by motor neurons via an autocrine manner to exert protective effects on motor neuron loss by ameliorating astrocytosis and microgliosis during amyotrophic lateral sclerosis (ALS) [104]. In anterior cingulate cortex (ACC), during chronic pain, CXCL13 and CXCR5 are both expressed in neurons. CXCL13 increases spontaneous excitatory postsynaptic currents (sEPSCs) in ACC and CXCR5 contributes to the increases in glutamatergic synaptic transmission [44]. In ipsilateral hemisphere, during ischemic stroke, CXCL13 is expressed on the inflamed cerebral vessels and recruits IL-21-producing T follicular helper (TFH) cells via activating CXCR5 expressed by these cells. IL-21 released from infiltrated TFH cells then activates interleukin-21 receptor (IL-21R) expressed on neurons to trigger neuronal death via Janus kinase (JAK)/STAT signaling [107]. The schematic picture was created with BioRender