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Deficiency of INPP4A promotes M2 macrophage polarization in eosinophilic chronic rhinosinusitis with nasal polyps

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Abstract

Objective

The treatment of eosinophilic chronic rhinosinusitis with nasal polyps (E-CRSwNP) remains a challenge due to its complex pathogenesis. Inositol polyphosphate-4-phosphatase type IA (INPP4A), a lipid phosphatase, has been implicated in allergic asthma. However, the expression and function of INPP4A in E-CRSwNP remain unclear. This study aims to investigate the role of INPP4A in macrophages in E-CRSwNP.

Methods

We assessed the expression of INPP4A in human and mouse nasal mucosal tissues via immunofluorescence staining. THP-1 cells were cultured and exposed to various cytokines to investigate the regulation of INPP4A expression and its functional role. Additionally, we established a murine nasal polyp (NP) model and administrated an INPP4A-overexpressing lentivirus evaluate its impact on NP.

Results

The percentage of INPP4A + CD68 + macrophages among total macrophages decreased in the E-CRSwNP group compared to the control and the non-eosinophilic CRSwNP (NE-CRSwNP) groups, exhibiting an inverse correlation with an increased percentage of CD206 + CD68 + M2 macrophages among total macrophages. Overexpression of INPP4A led to a reduced percentage of THP-1 cells polarizing towards the M2 phenotype, accompanied by decreased levels of associated chemotactic factors including CCL18, CCL22, CCL24, and CCL26. We also validated the involvement of the PI3K-AKT pathway in the function of INPP4A in vitro. Furthermore, INPP4A overexpression in the murine NP model resulted in the attenuation of eosinophilic inflammation in the nasal mucosa.

Conclusions

INPP4A deficiency promotes macrophage polarization towards the M2 phenotype, leading to the secretion of chemokines that recruit eosinophils and Th2 cells, thereby amplifying eosinophilic inflammation in E-CRSwNP. INPP4A may exert a suppressive role in eosinophilic inflammation and could potentially serve as a novel therapeutic strategy.

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Data availability

The data and materials used to support the findings of this study are available from the corresponding author upon request.

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Funding

National Natural Science Foundation of China (82271134, 81770986, 82071017); Fundamental Research Funds for the Central Universities (2042020kf1044, 2041022kf1113).

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Authors and Affiliations

  1. Department of Rhinology and Allergy, Otolaryngology-Head and Neck Surgery Center, Renmin Hospital of Wuhan University, 238 Jiefang Road, Wuhan, 430060, China

    Yingying Xu, Xiaoting Tong, Peiqiang Liu, Jingyu Huang, Siyuan Chen, Duo Liu, Tian Gu, Yulie Xie, Duo Guo & Yu Xu

  2. Hubei Province Key Laboratory of Allergy and Immunity, Wuhan, China

    Yu Xu

  3. Research Institute of Otolaryngology-Head and Neck Surgery, Renmin Hospital of Wuhan University, Wuhan, China

    Yu Xu

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  1. Yingying Xu
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Contributions

YX provided funding, supervision, writing-review and editing; YYX designed the study,performed experiments, analysed data and drafted original article; TXT, PQL, JYH, SYC,DL, TG,YLX and DG assessed, recorded the patients health information and collected the samples of participants; All authors discussed the results and commented on the manuscript.

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Correspondence to Yu Xu.

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Xu, Y., Tong, X., Liu, P. et al. Deficiency of INPP4A promotes M2 macrophage polarization in eosinophilic chronic rhinosinusitis with nasal polyps. Inflamm. Res. 73, 581–595 (2024). https://doi.org/10.1007/s00011-024-01855-y

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