Transcription factor IRF5 drives P2X4R+-reactive microglia gating neuropathic pain

Abstract

In response to neuronal injury or disease, microglia adopt distinct reactive phenotypes via the expression of different sets of genes. Spinal microglia expressing the purinergic P2X4 receptor (P2X4R) after peripheral nerve injury (PNI) are implicated in neuropathic pain. Here we show that interferon regulatory factor-5 (IRF5), which is induced in spinal microglia after PNI, is responsible for direct transcriptional control of P2X4R. Upon stimulation of microglia by fibronectin, IRF5 induced de novo expression of P2X4R by directly binding to the promoter region of the P2rx4 gene. Mice lacking Irf5 did not upregulate spinal P2X4R after PNI, and also exhibited substantial resistance to pain hypersensitivity. Furthermore, we found that expression of IRF5 in microglia is regulated by IRF8. Thus, an IRF8-IRF5 transcriptional axis may contribute to shifting spinal microglia toward a P2X4R-expressing reactive state after PNI. These results may provide a new target for treating neuropathic pain.

A novel P2X4 receptor-selective antagonist produces anti-allodynic effect in a mouse model of herpetic pain

“…Consistent with previous studies131429, spinal nerve transection produced a profound decrease in the withdrawal threshold of the hindpaw at 7 days post-surgery (Fig. 3a).…”

Blocking microglial pannexin-1 channels alleviates morphine withdrawal in rodents

“…4a) and YO-PRO-1 uptake (Fig. 1f) were recapitulated in a BV-2 microglial-like cell line 12 exposed to morphine for 5 d in vitro. Dye uptake was further potentiated in the presence of naloxone (10 µM) (Fig.…”

Transcriptional control of microglia phenotypes in health and disease

“…In spinal cord microglia, IRF8, in conjunction with IRF1 and IRF5, contributes to the induction of neuropathic pain after peripheral nerve injury (PNI) (71)(72)(73)(74). IRF8 expression is markedly upregulated by PNI, which results in hypersensitivity to pain (71).…”

“…IRF8 expression is markedly upregulated by PNI, which results in hypersensitivity to pain (71). IRF8 is upstream of IRF5, and Irf5-deficient mice exhibited substantial resistance to neuropathic pain (74). In microglia, IRF8 is also upstream of IRF1 and thereby regulates IL-1β expression after PNI (73).…”