2. Academic Validation
  3. Inhibition of AXL ameliorates pulmonary fibrosis via attenuation of M2 macrophage polarization

Inhibition of AXL ameliorates pulmonary fibrosis via attenuation of M2 macrophage polarization

  • Eur Respir J. 2025 Jan 9:2400615. doi: 10.1183/13993003.00615-2024.
Dong Ha Kim 1 2,  Kyungtaek Im 1 2,  In-Jeoung Baek 3,  Yun Jung Choi 1,  Hyeonjeong Lee 1,  Da-Som Kim 4,  Chae Won Lee 4,  JaeYi Jeong 4,  Kyosun Ban 4,  Sang-Yeob Kim 5,  Wonjun Ji 6,  Jae Cheol Lee 7,  Hyun-Yi Kim 8,  Yoonji Lee 9,  Yeongin Yang 9,  Miyong Yun 10,  Ho Cheol Kim 11,  Chang Min Choi 6 7,  Jin Kyung Rho 4 5
Affiliations

Affiliations

  • 1 Asan Institute for Life Sciences, Brain Korea 21 Project, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
  • 2 D. H. Kim and K.Im contributed equally to this work.
  • 3 Department of Cell and Genetic Engineering, Brain Korea 21 Project, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
  • 4 Department of Biochemistry and Molecular Biology, Brain Korea 21 Project, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
  • 5 Department of Convergence Medicine, Brain Korea 21 Project, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
  • 6 Department of Pulmonology and Critical Care Medicine, Brain Korea 21 Project, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
  • 7 Department of Oncology, Brain Korea 21 Project, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
  • 8 NGeneS Inc, Gyeonggi-do, South Korea.
  • 9 Qurient Co., Ltd, Gyeonggi-do, South Korea.
  • 10 Lab of Functional Aptamer, Department of Bioindustry and Bioresource Engineering, College of Life Sciences, Sejong University, Seoul, South Korea.
  • 11 Department of Pulmonology and Critical Care Medicine, Brain Korea 21 Project, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea kimhocheol10@gmail.com ccm@amc.seoul.kr jkrho@amc.seoul.kr.
PMID: 39788632 DOI: 10.1183/13993003.00615-2024
Abstract

Rationale: Although a relationship between the Gas6/Axl pathway and pulmonary fibrosis (PF) has been suggested, the precise mechanisms and clinical implications of the Axl pathway in idiopathic pulmonary fibrosis (IPF) are still unclear.

Methods: Constitutive and conditional AXL-knockout mice were generated and injected with bleomycin (BLM) to induce pulmonary fibrosis. The expression of Axl and macrophage subtypes in BLM-injected mice and patients with IPF was analysed using flow cytometry. The therapeutic effects of the Axl inhibitors were examined.

Results: AXL-deficient mice were resistant to BLM-induced pulmonary fibrosis and had a lower degree of M2-like macrophage differentiation than wild-type mice. Interestingly, Axl expression in monocytes was enhanced according to the progression of BLM-induced pulmonary fibrosis (PF), and these results were especially prominent in Ly6Chigh monocytes. Gene silencing or inhibitor treatment with Axl inhibited the differentiation of M2-like macrophages during bone marrow-derived macrophage (BMDMs) differentiation. These results were confirmed through experiments using Axlfl/flLysMCre+ mice and systems with depletion and reconstitution of macrophages. In line with these results, patients with severe IPF had higher Axl expression in monocytes, high GAS6 levels, and an enhanced population of M2-like macrophages than those with mild IPF. Lastly, treatment with Axl inhibitors ameliorated BLM-induced PF and improved survival rate.

Conclusions: The Axl pathway in classical monocytes contributed to PF progression through the induction of M2-like macrophage differentiation. Therefore, targeting Axl may be a promising therapeutic option for PF.

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