International immunopharmacology · 2025
Axl receptor tyrosine kinase inhibition ameliorates murine lupus diffuse alveolar hemorrhage by regulating macrophage activation.
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Pei Wenwen, Wang Ziye, Liang Renge, Yao Ranran, Liang Ruyu, Han Xiao, Xu Haojie, Sun Xiaolin, Su Yin
Аннотация
BACKGROUND: Macrophages play a crucial role in SLE associated diffuse alveolar hemorrhage (DAH), and Axl receptor tyrosine kinase (AxlTK) is prominently expressed in macrophages. This study aimed to evaluate the role of AxlTK in the onset of lupus-associated DAH.
METHODS: The expression of soluble Axl (sAxl) in serum from SLE patients with/without DAH was detected by ELISA. Wild-type (WT) and AxlTK-Knockout (Axl-KO) mice were used to explore the role of AxlTK in the development of DAH in a pristane-induced lupus model, and the therapeutic effect of AxlTK inhibitor TP-0903 was also assessed. The effect of AxlTK on macrophage function was demonstrated by flow cytometry and ELISA. The macrophages from the lung tissues of WT and Axl-KO DAH mice were collected for RNA-sequencing to further explore the mechanism.
RESULTS: The serum sAxl level was higher in SLE patients with DAH, and correlated with disease activity. And AxlTK was highly expressed on macrophages from the lungs of DAH mice. Compared with WT mice, both Axl-KO mice and TP-0903-treated mice exhibited less severe DAH, with reduced iNOS+F4/80+ macrophages and elevated CD206+F4/80+ macrophages in lung tissues. Further experiments revealed that AxlTK deficiency inhibited the polarization of bone marrow-derived macrophages (BMDMs) and decreased the uptake of apoptotic cells. Additionally, RNA-sequencing analysis revealed that AxlTK may affect macrophage activation in DAH mice through inflammatory pathways.
CONCLUSION: AxlTK is involved in the development of DAH by regulating the activation of macrophages and might be a potential therapeutic target for SLE with DAH.
METHODS: The expression of soluble Axl (sAxl) in serum from SLE patients with/without DAH was detected by ELISA. Wild-type (WT) and AxlTK-Knockout (Axl-KO) mice were used to explore the role of AxlTK in the development of DAH in a pristane-induced lupus model, and the therapeutic effect of AxlTK inhibitor TP-0903 was also assessed. The effect of AxlTK on macrophage function was demonstrated by flow cytometry and ELISA. The macrophages from the lung tissues of WT and Axl-KO DAH mice were collected for RNA-sequencing to further explore the mechanism.
RESULTS: The serum sAxl level was higher in SLE patients with DAH, and correlated with disease activity. And AxlTK was highly expressed on macrophages from the lungs of DAH mice. Compared with WT mice, both Axl-KO mice and TP-0903-treated mice exhibited less severe DAH, with reduced iNOS+F4/80+ macrophages and elevated CD206+F4/80+ macrophages in lung tissues. Further experiments revealed that AxlTK deficiency inhibited the polarization of bone marrow-derived macrophages (BMDMs) and decreased the uptake of apoptotic cells. Additionally, RNA-sequencing analysis revealed that AxlTK may affect macrophage activation in DAH mice through inflammatory pathways.
CONCLUSION: AxlTK is involved in the development of DAH by regulating the activation of macrophages and might be a potential therapeutic target for SLE with DAH.