Macrophage Toll-like Receptor 9 Contributes to Chemotherapy-Induced Neuropathic Pain in Male Mice

Abstract

Chemotherapy-induced peripheral neuropathy (CIPN) remains a pressing clinical problem; however, our understanding of sexual dimorphism in CIPN remains unclear. Emerging studies indicate a sex-dimorphic role of Toll-like receptor 4 (TLR4) in driving neuropathic pain. In this study, we examined the role of TLR9 in CIPN induced by paclitaxel in WT and Tlr9 mutant mice of both sexes. Baseline pain sensitivity was not affected in either Tlr9 mutant male or female mice. Intraplantar and intrathecal injection of the TLR9 agonist ODN 1826 induced mechanical allodynia in both sexes of WT and Tlr4 KO mice but failed to do so in Tlr9 mutant mice. Moreover, Trpv1 KO or C-fiber blockade by resiniferatoxin failed to affect intraplantar ODN 1826-induced mechanical allodynia. Interestingly, the development of paclitaxel-evoked mechanical allodynia was attenuated by TLR9 antagonism or Tlr9 mutation only in male mice. Paclitaxel-induced CIPN caused macrophage infiltration to DRGs in both sexes, and this infiltration was not affected by Tlr9 mutation. Paclitaxel treatment also upregulated TNF and CXCL1 in macrophage cultures and DRG tissues in both sexes, but these changes were compromised by Tlr9 mutation in male animals. Intraplantar adoptive transfer of paclitaxel-activated macrophages evoked mechanical allodynia in both sexes, which was compromised by Tlr9 mutation or by treatment with TLR9 inhibitor only in male animals. Finally, TLR9 antagonism reduced paclitaxel-induced mechanical allodynia in female nude mice (T-cell and B-cell deficient). Together, these findings reveal sex-dimorphic macrophage TLR9 signaling in chemotherapy-induced neuropathic pain.

IL-4 induces M2 macrophages to produce sustained analgesia via opioids

“…remains to be clarified, it appears that opioid-dependent actions of IL-4 and M2 macrophages are mainly beneficial in diminishing mechanical hypersensitivity. Because we used male mice, it will also be important to examine females, since the involvement of macrophages in pain may be sex dependent (56).…”

Microglial depletion under thalamic hemorrhage ameliorates mechanical allodynia and suppresses aberrant axonal sprouting

“…Although minocycline is commonly used to halt microglial activity, it has a nonspecific effect on macrophages, T cells, neuronal cells (30)(31)(32)(33), and even on astrocytes (34); all of them are suggested to be involved in the pathogenesis of neuropathic pain (22,(35)(36)(37)(38)(39)(40)(41). In contrast, treatment with a CSF1R inhibitor results in effective ablation of microglia with minor effect on other cells (25)(26)(27)(28), which is also supported by our flow cytometry data, although we cannot fully exclude the possible influence of PLX3397 treatment on peripheral CSF1R-positive circulating myeloid cells.…”

TLR8 in the trigeminal ganglion contributes to the maintenance of trigeminal neuropathic pain

“…In recent years, the role of TLRs in pain and itch has been widely investigated [14,31]. Several TLRs have been demonstrated to be expressed in glial cells or neurons in the DRG in chronic pain conditions [15,32]. For example, TLR9 is expressed in DRG macrophages and contributed to chemotherapy-induced neuropathic pain [15].…”

“…Several TLRs have been demonstrated to be expressed in glial cells or neurons in the DRG in chronic pain conditions [15,32]. For example, TLR9 is expressed in DRG macrophages and contributed to chemotherapy-induced neuropathic pain [15]. TLR3 is expressed in small-diameter TRPV1-positive DRG neurons and regulates sensory neuronal excitability [33].…”

“…However, evidence shows that TLR7 is localized on the membrane of DRG neurons and regulates itch transmission [14]. Recently, TLR9 was found to be expressed in the DRG macrophages and contributed to neuropathic pain induced by paclitaxel in male mice [15]. Tlr8 and Tlr7 genes show high homology to each other and are both located on the X chromosome.…”