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. 2023 May:118:110070.
doi: 10.1016/j.intimp.2023.110070. Epub 2023 Mar 30.

TREM2 Insufficiency Protects against Pulmonary Fibrosis by Inhibiting M2 Macrophage Polarization

Qiujie Luo  1 , Dawei Deng  1 , Yang Li  1 , Hongjie Shi  1 , Jinping Zhao  1 , Qiaofeng Qian  1 , Wei Wang  1 , Jie Cai  1 , Wenjun Yu  2 , Jinping Liu  3
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Free article

TREM2 Insufficiency Protects against Pulmonary Fibrosis by Inhibiting M2 Macrophage Polarization

Qiujie Luo et al. Int Immunopharmacol. 2023 May.
Free article

Abstract

Rationale Idiopathic pulmonary fibrosis (IPF) is a lung disease with high mortality, limited treatment options and an unknown aetiology. M2 macrophages play a critical role in the pathological process of IPF. Triggering receptor expressed on myeloid cells-2 (TREM2) participates in the regulation of macrophages, although its role in IPF remains elusive.

Methods: This study examined the role of TREM2 in macrophage regulation using a well-established bleomycin (BLM)-induced pulmonary fibrosis (PF) mouse model. TREM2 insufficiency was induced by intratracheal treatment with TREM2-specific siRNA. The effects of TREM2 on IPF were evaluated using histological staining and molecular biological methods.

Results: TREM2 expression levels were significantly elevated in the lungs of IPF patients and mice with BLM-induced pulmonary fibrosis mice. Bioinformatics analysis revealed that IPF patients with higher TREM2 expression had a shorter survival time, and that TREM2 expression was closely associated with fibroblasts and M2 macrophages. Gene Ontology (GO) enrichment analysis showed that found TREM2-related differentially expressed genes (DEGs) were associated with inflammatory responses, extracellular matrix (ECM) and collagen formation. Single-cell RNA sequencing analysis revealed that TREM2 was predominantly expressed in macrophages. TREM2 insufficiency inhibited BLM-induced pulmonary fibrosis and M2 macrophage polarization. Mechanistic studies showed that TREM2 insufficiency suppressed the activation of STAT6 and the expression of fibrotic factors such as Fibronectin (Fib), Collagen I (Col I) and α- smooth muscle actin (α-SMA).

Conclusion: Our study showed that TREM2 insufficiency might alleviate pulmonary fibrosis possibly through macrophage polarization regulation via STAT6 activation, providing a promising macrophage-related approach for the clinical therapy of pulmonary fibrosis.

Keywords: Fibrosis; M2 macrophage; Macrophage polarization; Pulmonary fibrosis; Triggering receptor expressed on myeloid cells 2 (TREM2).

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Conflict of interest statement

Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.