Aging-Related Phenotypic Conversion of Medullary Microglia Enhances Intraoral Incisional Pain Sensitivity.

Daisuke Ikutame,Toshimitsu Iinuma,Shintaro Fujiwara,Suzuro Hitomi,Tatsuki Oto,Kentaro Urata,Masamichi Shinoda,Yoshinori Hayashi,Ikuko Shibuta,Koichi Iwata

doi:10.3390/ijms21217871

Abstract

Activated microglia involved in the development of orofacial pain hypersensitivity have two major polarization states. The aim of this study was to assess the involvement of the aging-related phenotypic conversion of medullary microglia in the enhancement of intraoral pain sensitivity using senescence-accelerated mice (SAM)-prone/8 (SAMP8) and SAM-resistant/1 (SAMR1) mice. Mechanical head-withdrawal threshold (MHWT) was measured for 21 days post palatal mucosal incision. The number of CD11c-immunoreactive (IR) cells [affective microglia (M1)] and CD163-IR cells [protective microglia (M2)], and tumor-necrosis-factor-α (TNF-α)-IR M1 and interleukin (IL)-10-IR M2 were analyzed via immunohistochemistry on days 3 and 11 following incision. The decrease in MHWT observed following incision was enhanced in SAMP8 mice. M1 levels and the number of TNF-α-IR M1 were increased on day 3 in SAMP8 mice compared with those in SAMR1 mice. On day 11, M1 and M2 activation was observed in both groups, whereas IL-10-IR M2 levels were attenuated in SAMP8 mice, and the number of TNF-α-IR M1 cells increased, compared to those in SAMR1 mice. These results suggest that the mechanical allodynia observed following intraoral injury is potentiated and sustained in SAMP8 mice due to enhancement of TNF-α signaling, M1 activation, and an attenuation of M2 activation accompanying IL-10 release.

Highlights

Aging is a progressive biological process characterized by neurological dysfunction, such as cognitive impairment [1]
By day 11, Mechanical head-withdrawal threshold (MHWT) levels in SAMR1 mice had returned to those seen in naive mice, SAMP8 incision mice still showed a significant decrease in MHWT compared to that in naive SAMP8 mice (SAMR1 incision mice (45.5 ± 1.0), SAMR1 naive mice (46.0 ± 0.9), SAMP8 incision mice (35.0 ± 1.7), and SAMP8 naive mice (44.0 ± 0.8))
Overall, comparing the effects in SAMP8 and SAMR1 incision mice, MHWT levels in the SAMP8 incision mice remained low compared with those in SAMR1 incision mice through the experimental period, and did not return to those seen in SAMP8 naive mice

Summary

Introduction

Aging is a progressive biological process characterized by neurological dysfunction, such as cognitive impairment [1]. Microglial activation is known to modulate nociceptive neuronal excitability in the spinal dorsal horn in response to peripheral pathogenesis, such as sciatic nerve injury [5,6,7,8,9,10]. Affective microglia (M1) are characterized by the production of pro-inflammatory mediators, including interleukin (IL)-1β, tumor necrosis factor-α (TNF-α), and IL-6 [17]. Microglia play dual roles in regulating the onset of inflammation through M1 and switch to an M2 phenotype to promote healing and repair. It is unclear whether age-related neurodegenerative affects the polarity changes of microglia in situations orofacial pathogenesis and if the polarity changes modulate orofacial pain hypersensitivity

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