Unconventional Role of Caspase-6 in Spinal Microglia Activation and Chronic Pain

Figure 1

Microglial reactivity to nerve injury and signaling in chronic pain. (a) Nerve injury induces CX3CR1 expression in spinal microglia of mice expressing GFP under the control of CX3CR1 promoter. (b) Tissue and nerve injury results in the release of ATP, CX3CL1, and CSF1 leading to the activation of microglia shown by the phosphorylation of p38 and pERK and the production of prostaglandins, cytokines, and growth factors (e.g., TNFα and BDNF). Microglial cells also produce the cytokine IL-1b via the cathepsin/caspase-1 pathway, which can be further activated by binding to IL-1R1. (c) Microglial cytokines, prostaglandins, and growth factors modulate excitatory (glutamatergic synapses—GLU/NMDA and AMPA receptors) and inhibitory (GABAergic and glycinergic synapses—GABA/GABAR and GLY/GLYR) synaptic transmission. For instance, BDNF produces disinhibition of GABAergic lamina I neurons leading to chronic pain.

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