RRC ID 81864
Author He G, Ni Y, Hua R, Wan H, Tan Y, Chen Q, Xu S, Yang Y, Zhang L, Shu W, Huang KB, Mo Y, Liang H, Chen M.
Title Latexin deficiency limits foam cell formation and ameliorates atherosclerosis by promoting macrophage phenotype differentiation.
Journal Cell Death Dis
Abstract Latexin (LXN) is abundant in macrophages and plays critical roles in inflammation. Much is known about macrophages in atherosclerosis, the role of macrophage LXN in atherosclerosis has remained elusive. Here, the expression of LXN in human and mouse atherosclerotic lesions was examined by immunofluorescence and immunohistochemistry. LXN knockout and LXN/ApoE double-knockout mice were generated to evaluate the functions of LXN in atherosclerosis. Bone marrow transplantation (BMT) experimentation was carried out to determine whether macrophage LXN regulates atherosclerosis. We found that LXN is enriched in human and murine atherosclerotic lesions, mainly localized to macrophages. LXN deletion ameliorated atherosclerosis in ApoE-/- mice. BMT demonstrate that deletion of LXN in bone marrow protects ApoE-/- mice against atherosclerosis. Mechanistically, we found that LXN targets and inhibits JAK1 in macrophages. LXN deficiency stimulates the JAK1/STAT3/ABC transporter pathway, thereby enhancing the anti-inflammatory and anti-oxidant phenotype, cholesterol efflux, subsequently minimizing foam cell formation and atherosclerosis. Gene therapy by treatment of atherosclerotic mice with adeno-associated virus harbouring LXN-depleting shRNA attenuated the disease phenotype. In summary, our study provides new clues for the role of LXN in the pathological regulation of atherosclerosis, and determines that LXN is a target for preventing atherosclerosis, which may be a potential new anti-atherosclerosis therapeutic target.
Volume 15(10)
Pages 754
Published 2024-10-18
DOI 10.1038/s41419-024-07141-3
PII 10.1038/s41419-024-07141-3
PMID 39424784
MeSH Animals Apolipoproteins E / deficiency Apolipoproteins E / genetics Apolipoproteins E / metabolism Atherosclerosis* / genetics Atherosclerosis* / metabolism Atherosclerosis* / pathology Cell Differentiation Foam Cells* / metabolism Foam Cells* / pathology Humans Macrophages* / metabolism Male Mice Mice, Inbred C57BL Mice, Knockout Phenotype* STAT3 Transcription Factor / metabolism
Resource
Mice RBRC03456