Science: The function of microglia is being tapped again! Studies have revealed its involvement in the relief of neuropathic pain

Peripheral nerve damage causes neuropathic pain by affecting neurons and glial cells

On March 31, 2022, Professor Makoto Tsuda's team at the Institute of Pharmacy of Kyushu University published a report in Science that used a mouse model of peripheral nerve injury to reveal that the posterior corner CD11c+ microglia of the spinal cord are involved in spontaneous pain relief

CD11c+ microglia for

Spontaneous relief of neuropathic pain is necessary

The researchers first used Itgax-Venus mice (Itgax encoding CD11c) to construct a peripheral nerve injury model (PNI) and found that PNI significantly increased the number of Venus+ cells, and that Venus was limited to the tdT+ cells of IBA1+, CD11b+, P2Y12R+, HexbtdT/tdT mice (Hexb was limited to microglia).

As supplementary data, the researchers also used bone marrow chimeric mice and spleen excision mice, ruling out the possibility

Flow cytometry results showed that CD11c+ microglia peaked on day 14 postoperative PNI and remained at high levels

Using Itgax-DTR-EGFP mice further, the researchers specifically removed CD11c+ microglia by intrathecal DTX injection after day 14 of PNI and found that mice that removed CD11c+ microglia did not show spontaneous pain relief

Figure 1: Necessity of spinal cord CD11c+ microglia for spontaneous pain relief

CD11c+ microglia

Spontaneous pain relief is caused by IGF1

To explore what molecules CD11c+ microglia play a role in, the researchers performed RNA sequencing of CD11chigh and CD11cneg microglia in the spinal cord after PNI, and the results showed that the expression of Igf1 in CD11chigh was significantly higher than that in CD11cneg

The specific removal of CD11c+ microglia by Itgax-Cre; Igf1flox/flox mice, the specific knockout of Igf1 in microglia by Cx3cr1CreERT2; the specific knockout of microglia in Igf1flox/flox mice, or the injection of IGF1 neutralizing antibodies into wild-type mice all significantly inhibited spontaneous pain relief

The above results suggest that elevated IGF1 in CD11c+ microglia is necessary

Figure 2: Necessity of IGF1 in CD11c+ microglia for spontaneous pain relief

Myelination results in CD11c+

Increase in microglia

So, what causes an increase in CD11c+ microglia? The researchers found that plantar injection of saporin-CTB (injury to myelinated nerve fibers) led to an increase in spinal cord CD11c+ microglia, while plantar injection of saporin-IB4 (which damages myelin-free nerve fibers) did not

After the isolation of PNI, CD11c+ microglia were cultured in vitro, and the researchers found that the phagocytosis of the cells on the myelin sheath was significantly elevated; MBP was co-labeled with Venus (showing CD11c expression) and CD68 (showing lysosomes) after immunohistochemistry; Electron microscopy pictures show CD11c+ microglia

In addition, Axl associated with myelin phagocytosis is significantly elevated in CD11c+ microglia

Thus, the above results suggest that Axl may lead to an increase in CD11c+ microglia through myelin phagocytosis

Figure 3: Axl leads to an increase in CD11c+ microglia

Specific removal of CD11c+ microglia

Causes pain to recur

After day 35 of PNI, the evasion threshold has returned to baseline levels

Similarly, the use of Cx3cr1CreERT2;Igf1flox/flox mice in PNI days 37 and 39 specifically knockout microglia Igf1, or intrasheath injection of IGF1 neutralizing antibodies in wild-type mice, both resulted in pain recurrence

Figure 4: Removal of CD11c+ microglia after spontaneous relief of PNI pain leads to pain recurrence

Summary

In summary, the study revealed that CD11c+ microglia play a role in inhibiting pain in the later stages of neuropathic pain through IGF1, achieving spontaneous pain relief

Unlike previous studies that fully revealed the "pain-producing" role of microglia in neuropathic pain, this study revealed that there are still subsets of microglia that exert "analgesic" effects, providing evidence for the heterogeneity of microglia and also enlightening us to re-examine the function of
microglia.

Figure 5: Different microglial subsets in neuropathic pain

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