SIRT5 exacerbates eosinophilic chronic rhinosinusitis by promoting polarization of M2 macrophage - 26/06/24

Doi : 10.1016/j.jaci.2024.04.028

Xu-Dong Cha, BS ^a, Qing-Yun Zou, MM ^c, Feng-Zhen Li, MM ^a, Tian-Yu Wang, MM ^a, Sheng-Lei Wang, MM ^a, Bo-Yu Cai, MM ^a, Zhi-Wen Cao, MM ^a, Zhen-Hua Ji, MM ^a, Hai-Bin Liu, MM ^a, Wen-Wen Wang, BS ^b, Teng-Fei Li, MM ^a, Cai-Quan Liang, MD ^a,^⁎ , Wen-Wen Ren, PhD ^a,^⁎ , Huan-Hai Liu, MM ^a,^⁎
^a Department of Otolaryngology, the Second Affiliated Hospital of the Naval Medical University (Shanghai Changzheng Hospital), Shanghai, China
^b Department of Neurology, the Second Affiliated Hospital of the Naval Medical University (Shanghai Changzheng Hospital), Shanghai, China
^c Department of Otolaryngology, Naval Medical Center, Naval Medical University, Shanghai, China

^∗Corresponding authors: Cai-Quan Liang, MD, Wen-Wen Ren, PhD, or Huan-Hai Liu, MM, Department of Otolaryngology–Head and Neck Surgery, Shanghai Changzheng Hospital, the Second Affiliated Hospital of the Naval Medical University, No. 415 Fengyang Rd, Shanghai 200003, China.Department of Otolaryngology–Head and Neck SurgeryShanghai Changzheng HospitalThe Second Affiliated Hospital of the Naval Medical UniversityNo. 415 Fengyang RdShanghai430030China

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Graphical abstract

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Abstract

Background

Previous studies implied that local M2 polarization of macrophage promoted mucosal edema and exacerbated T_H2 type inflammation in chronic rhinosinusitis with nasal polyps (CRSwNP). However, the specific pathogenic role of M2 macrophages and the intrinsic regulators in the development of CRS remains elusive.

Objective

We sought to investigate the regulatory role of SIRT5 in the polarization of M2 macrophages and its potential contribution to the development of CRSwNP.

Methods

Real-time reverse transcription–quantitative PCR and Western blot analyses were performed to examine the expression levels of SIRT5 and markers of M2 macrophages in sinonasal mucosa samples obtained from both CRS and control groups. Wild-type and Sirt5-knockout mice were used to establish a nasal polyp model with T_H2 inflammation and to investigate the effects of SIRT5 in macrophage on disease development. Furthermore, in vitro experiments were conducted to elucidate the regulatory role of SIRT5 in polarization of M2 macrophages.

Results

Clinical investigations showed that SIRT5 was highly expressed and positively correlated with M2 macrophage markers in eosinophilic polyps. The expression of SIRT5 in M2 macrophages was found to contribute to the development of the disease, which was impaired in Sirt5-deficient mice. Mechanistically, SIRT5 was shown to enhance the alternative polarization of macrophages by promoting glutaminolysis.

Conclusions

SIRT5 plays a crucial role in promoting the development of CRSwNP by supporting alternative polarization of macrophages, thus providing a potential target for CRSwNP interventions.

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Key words : SIRT5, M2 macrophages, chronic rhinosinusitis, NPs, T_H2

Abbreviations used : Arg1, BM, BM-M2, CRS, CRSsNP, CRSwNP, Ctrl, ECRS, EM, FXIII-A, GLUD1, H3K27me3, IHC, IT, MBP, mRNA, Non-ECRS, NP, OVA, OXPHOS, PBS, RT-qPCR, SEB, Sirt, WT, αKG