Protectin DX resolves fracture-induced postoperative pain in mice via neuronal signaling and GPR37-activated macrophage efferocytosis
Yize Li, Sangsu Bang, Jasmine Ji, Jing Xu, Min Lee, Sharat Chandra, Charles N. Serhan, Ru-Rong Ji
Yize Li, Sangsu Bang, Jasmine Ji, Jing Xu, Min Lee, Sharat Chandra, Charles N. Serhan, Ru-Rong Ji
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Research Article Cell biology Neuroscience

Protectin DX resolves fracture-induced postoperative pain in mice via neuronal signaling and GPR37-activated macrophage efferocytosis

Abstract

Protectin DX (PDX) is a member of the superfamily of specialized proresolving mediators and exerts anti-inflammatory actions in animal models; however, its signaling mechanism remains unclear. Here, we demonstrate the analgesic actions of PDX in a mouse model of tibial fracture–induced postoperative pain (fPOP). Intravenous early- and late-phase treatment of PDX (100 ng/mouse) effectively alleviated fPOP. Compared with protectin D1 (PD1)/neuroprotectin D1, DHA, steroids, and meloxicam, PDX provided superior pain relief. While dexamethasone and meloxicam prolonged fPOP, PDX shortened the pain duration. The analgesic effects of PDX were abrogated in Gpr37−/− mice, which displayed deficits in fPOP resolution. PDX was shown to bind GPR37 and induce calcium responses in peritoneal macrophages. LC-MS/MS–based lipidomic analysis revealed that endogenous PDX levels were approximately 10-fold higher than those of PD1 in muscle at the fracture site. PDX promoted macrophage polarization via GPR37-dependent phagocytosis and efferocytosis through calcium signaling in vitro, and it further enhanced macrophage viability and efferocytosis in vivo via GPR37. Finally, PDX rapidly modulated nociceptor neuron responses by suppressing C-fiber–induced muscle reflex in vivo and calcium responses in DRG neurons ex vivo and by reducing TRPA1/TRPV1-induced acute pain and neurogenic inflammation in vivo. Our findings highlight multiple benefits of PDX to manage postoperative pain and promote perioperative recovery.

Authors

Yize Li, Sangsu Bang, Jasmine Ji, Jing Xu, Min Lee, Sharat Chandra, Charles N. Serhan, Ru-Rong Ji

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Figure 1

Perisurgical pre- and posttreatment PDX attenuates tibial fPOP in CD1 mice.

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Perisurgical pre- and posttreatment PDX attenuates tibial fPOP in CD1 mi...
(A) Schematic of the tibial fracture model and PDX pretreatment timeline. CD1 mice received 2 i.v. injections of PDX (100 ng, 100 μL) or PBS (100 μL): 1 immediately before fracture surgery and 1 after fracture day 2. BL, baseline. (B–E) Effects of PDX and vehicle on fPOP measured on postsurgical days 1, 3, 5, and 7, including mechanical pain (PWT by von Frey test; B), thermal pain (paw withdrawal latency by Hargreaves test; C), cold pain (duration of pain with lifting/licking behavior in acetone test; D), and spontaneous pain (duration of lifting/licking behavior; E). (F) Posttreatment paradigm. In a separate cohort, mice received a single i.v. injection of PDX (100 ng, 100 μL) or PBS on postfracture day 10. (G–I) Posttreatment PDX also reduced mechanical (G), thermal (H), and cold (I) pain. (J and K) Comparison of PDX with other SPMs (NPD1, RvD5, and MaR1; 300 ng/mouse) and DHA (300 μg/mouse; J), as well as anti-inflammatory drugs (dexamethasone, 0.5 mg/kg; meloxicam, 10 mg/kg) and gabapentin (30 mg/kg; K). (L) Route-of-administration comparison showing effective analgesia following i.t. (10 ng), p.SN. (20 ng), i.v. (100 ng), i.p. (150 ng), or p.o. (1 μg) delivery of PDX. Data in J–L are presented as AUC of PWT. Data are presented as mean ± SEM. Statistics: 2-way ANOVA with Bonferroni’s post hoc test (B–E and G–I) and 1-way ANOVA with Tukey’s post hoc test (J–L). **P < 0.01, ***P < 0.001, ****P < 0.0001; n = 10 (B–E and G–I), n = 6 (J–L); equal number of male and female mice; triangles, male; circles, female.