The immunomodulatory effect of IL-4 accelerates bone substitute material-mediated osteogenesis in aged rats via NLRP3 inflammasome inhibition

Duchenhui Li; Xiao Li; Jie Zhang; Zhenglong Tang; Ai Tian

doi:10.3389/fimmu.2023.1121549

The immunomodulatory effect of IL-4 accelerates bone substitute material-mediated osteogenesis in aged rats via NLRP3 inflammasome inhibition

Front Immunol. 2023 Apr 20:14:1121549. doi: 10.3389/fimmu.2023.1121549. eCollection 2023.

Authors

Duchenhui Li^{1

2

3}, Xiao Li⁴, Jie Zhang¹, Zhenglong Tang^{2

3}, Ai Tian¹

Affiliations

¹ Department of Prosthodontics and Implantology, School and Hospital of Stomatology of Guizhou Medical University, Guiyang, Guizhou, China.
² Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology of Guizhou Medical University, Guiyang, China.
³ Department of Physiology and Pathology, School of Basic Medical Sciences, Guizhou Medical University, Guiyang, China.
⁴ Department of Oral and Maxillofacial Surgery, Guiyang Hospital of Stomatology, Guiyang, Guizhou, China.

Abstract

Background: Bone defect repair by implanting bone substitute materials has been a common clinical treatment. With the understanding of substance-immune system interactions and increasing evidence indicating that the post-implantation immune response determines the fate of bone substitute materials, active modulation of host macrophage polarization is considered a promising strategy. However, whether the same regulatory effects exist when an individual immune system is altered with aging is unclear.

Methods: In this study, we mechanistically investigated the effect of immunosenescence on the active regulation of macrophage polarization by establishing a cranial bone defect model in young and aged rats implanted with Bio-Oss®. Forty-eight young and 48 aged specific pathogen-free (SPF) male SD rats were randomly divided into two groups. In the experimental group, 20 μL of IL-4 (0.5 μg/mL) was injected locally on the third to seventh postoperative days, while an equal volume of PBS was injected in the control group. Specimens were collected at 1, 2, 6, and 12 weeks postoperatively, and bone regeneration at the defect site was evaluated by micro-CT, histomorphometry, immunohistochemistry, double-labeling immunofluorescence, and RT-qPCR.

Results: The application of exogenous IL-4 reduced activation of NLRP3 inflammasomes by promoting the polarization of M1 macrophages to M2 macrophages, thus promoting bone regeneration at the site of bone defects in aged rats. However, this effect was gradually weakened after the IL-4 intervention was discontinued.

Conclusion: Our data confirmed that a strategy to regulate macrophage polarization is also feasible under conditions of immunosenescence, i.e., the local inflammatory microenvironment can be regulated by reducing M1-type macrophages. However, further experiments are needed to determine an exogenous IL-4 intervention that can maintain a more sustained effect.

Keywords: bone substitutes materials; immunomodulation; immunosenescence; macrophages; osteogenesis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Bone Substitutes* / pharmacology
Inflammasomes
Interleukin-4 / pharmacology
Male
NLR Family, Pyrin Domain-Containing 3 Protein
Osteogenesis*
Rats
Rats, Sprague-Dawley

Substances

Inflammasomes
NLR Family, Pyrin Domain-Containing 3 Protein
Bone Substitutes
Interleukin-4
Nlrp3 protein, rat

Grants and funding

This work was supported by the National Natural Science Foundation of China, No. 81760192 (to AT); the National Natural Science Foundation of China, No. 82260193 (to AT); and the Joint Fund of Guiyang Science and Technology Bureau, No. [2018]1-82 (to AT).