Macrophage-derived semaphorin 7A drives atherosclerosis via the integrin β1/JNK/MSR1 axis

Abstract

Atherosclerosis is a chronic inflammatory disease driven by pathological processes such as macrophage foam cell formation. Semaphorin 7A (SEMA7A) is an immunoregulatory signaling molecule known to modulate immune responses and cellular adhesion. However, the contribution of macrophage-derived SEMA7A to atherogenesis has yet to be fully elucidated. In this study, we analyzed gene expression profiles of human mononuclear cells from the Gene Expression Omnibus (GEO) database and revealed highly expressed SEMA7A and its receptor integrin β1 in macrophages. The upregulation of SEMA7A and integrin β1 was also observed during the differentiation of THP-1 monocytes into macrophages. Mice with macrophage-specific deletion of Sema7a showed a 57.2% reduction in atherosclerotic lesion size and improved plaque stability in atherosclerosis mouse model compared to control mice. Mechanistically, macrophage SEMA7A promoted the expression of macrophage scavenger receptor 1 (MSR1) and lipid uptake mediated by integrin β1 and downstream JNK signaling pathway in macrophages. Notably, pharmacological inhibition of integrin β1 with integrin receptor antagonist GLPG0187 effectively suppressed atherosclerosis progression. These findings identify macrophage-derived SEMA7A as a key driver of atherosclerosis through a novel integrin β1/JNK/MSR1 axis, providing potential targets for the prevention and treatment of atherosclerosis.

Keywords

atherosclerosis / macrophage / SEMA7A / lipid uptake

References

[1] Zhao D , Liu J , Wang M , Zhang X , Zhou M . Epidemiology of cardiovascular disease in China: current features and implications. Nat Rev Cardiol 2019; 16(4): 203–212

[2] Jimenez-Trinidad FR , Calvo-Gomez S , Sabate M , Brugaletta S , Campuzano V , Egea G , Dantas AP . Extracellular vesicles as mediators of endothelial dysfunction in cardiovascular diseases. Int J Mol Sci 2025; 26(3): 1008

[3] Dong Z , Jin Y , Shen Y , Huang J , Tan J , Feng Q , Gong Z , Zhu S , Chen H , Yu F , Li W , Jia Y , Kong W , Fu Y . METTL3-catalyzed m6A methylation facilitates the contribution of vascular smooth muscle cells to atherosclerosis. Cardiovasc Res 2025; 121(4): 568–584

[4] Xu S , Yang B , Yu W , Gao Y , Cai H , Wang Z . TREM2 as a therapeutic target in atherosclerosis. Cell Biol Int 2025; 49(4): 305–316

[5] Fang F , Wang E , Fang M , Yue H , Yang H , Liu X . Macrophage-based pathogenesis and theranostics of vulnerable plaques. Theranostics 2025; 15(4): 1570–1588

[6] Xiang X , Zhang F , Nie L , Guo X , Qin M , Chen J , Jiang D , Zhang Z , Mao L . Legumain deficiency halts atherogenesis by modulating T cell receptor signaling. Aging Cell 2025; 24(2): e14391

[7] Guo Z , Zhang W , Gao H , Li Y , Li X , Yang X , Fan L . High expression levels of haem oxygenase-1 promote ferroptosis in macrophage-derived foam cells and exacerbate plaque instability. Redox Biol 2024; 76: 103345

[8] Libby P , Ridker PM , Hansson GK . Progress and challenges in translating the biology of atherosclerosis. Nature 2011; 473(7347): 317–325

[9] Li S , Navia-Pelaez JM , Choi SH , Miller YI . Macrophage inflammarafts in atherosclerosis. Curr Opin Lipidol 2023; 34(5): 189–195

[10] Chen Y , Zhang J , Cui W , Silverstein RL . CD36, a signaling receptor and fatty acid transporter that regulates immune cell metabolism and fate. J Exp Med 2022; 219(6): e20211314

[11] Liu Y , Tang X , Yuan H , Gao R . Naringin inhibits macrophage foam cell formation by regulating lipid homeostasis and metabolic phenotype. Nutrients 2024; 16(9): 1321

[12] Pasterkamp RJ , Peschon JJ , Spriggs MK , Kolodkin AL . Semaphorin 7A promotes axon outgrowth through integrins and MAPKs. Nature 2003; 424(6947): 398–405

[13] Pasterkamp RJ , Kolk SM , Hellemons AJ , Kolodkin AL . Expression patterns of semaphorin7A and plexinC1 during rat neural development suggest roles in axon guidance and neuronal migration. BMC Dev Biol 2007; 7(1): 98

[14] Eixarch H , Gutierrez-Franco A , Montalban X , Espejo C . Semaphorins 3A and 7A: potential immune and neuroregenerative targets in multiple sclerosis. Trends Mol Med 2013; 19(3): 157–164

[15] CantóE M , Tintore LM , Villar E , Borras JC , Alvarez-Cermeno C , Chiva E , Sabido A , Rovira X , Montalban M . Validation of semaphorin 7A and ala-beta-his-dipeptidase as biomarkers associated with the conversion from clinically isolated syndrome to multiple sclerosis. J Neuroinflammation 2014; 11(1): 181

[16] Tarullo SE , Hill RC , Hansen KC , Behbod F , Borges VF , Nelson AC , Lyons TR . Postpartum breast cancer progression is driven by semaphorin 7a-mediated invasion and survival. Oncogene 2020; 39(13): 2772–2785

[17] Garcia-Areas R , Libreros S , Simoes M , Castro-Silva C , Gazaniga N , Amat S , Jaczewska J , Keating P , Schilling K , Brito M , Wojcikiewicz EP , Iragavarpu-Charyulu V . Suppression of tumor-derived Semaphorin 7A and genetic ablation of host-derived Semaphorin 7A impairs tumor progression in a murine model of advanced breast carcinoma. Int J Oncol 2017; 51(5): 1395–1404

[18] Granja T , Kohler D , Tang L , Burkard P , Eggstein C , Hemmen K , Heinze KG , Heck-Swain KL , Koeppen M , Gunther S , Blaha M , Magunia H , Bamberg M , Konrad F , Ngamsri KC , Fuhr A , Keller M , Bernard AM , Haeberle HA , Bakchoul T , Zarbock A , Nieswandt B , Rosenberger P . Semaphorin 7A coordinates neutrophil response during pulmonary inflammation and sepsis. Blood Adv 2024; 8(11): 2660–2674

[19] Lu Q , Liu Z , Zhao L , Xu L , Liu C , Li L , Cao Y , Li F , Wu L , Wang L , Chen T , You T , Ren L , Wang G , Tang C , Zhu L . Sema7A protects against high-fat diet-induced obesity and hepatic steatosis by regulating adipo/lipogenesis. Mol Metab 2023; 70: 101698

[20] Hu S , Liu Y , You T , Heath J , Xu L , Zheng X , Wang A , Wang Y , Li F , Yang F , Cao Y , Zhang H , van Gils JM , van Zonneveld AJ , Jo H , Wu Q , Zhang Y , Tang C , Zhu L . Vascular semaphorin 7A upregulation by disturbed flow promotes atherosclerosis through endothelial beta1 integrin. Arterioscler Thromb Vasc Biol 2018; 38(2): 335–343

[21] Köhler D , Granja T , Volz J , Koeppen M , Langer HF , Hansmann G , Legchenko E , Geisler T , Bakchoul T , Eggstein C , Haberle HA , Nieswandt B , Rosenberger P . Red blood cell-derived semaphorin 7A promotes thrombo-inflammation in myocardial ischemia-reperfusion injury through platelet GPIb. Nat Commun 2020; 11(1): 1315

[22] Hu S , Liu Y , You T , Zhu L . Semaphorin 7A promotes VEGFA/VEGFR2-mediated angiogenesis and intraplaque neovascularization in ApoE^−/− mice. Front Physiol 2018; 9: 1718

[23] Hong L , Li F , Tang C , Li L , Sun L , Li X , Zhu L . Semaphorin 7A promotes endothelial to mesenchymal transition through ATF3 mediated TGF-beta2/Smad signaling. Cell Death Dis 2020; 11(8): 695

[24] Song X , Gao F , Li H , Qin W , Chai C , Shi G , Yang H . Semaphorin 7A promotes human vascular smooth muscle cell proliferation and migration through the β-catenin signaling pathway. Biocell 2023; 47(4): 849–858

[25] Suzuki K , Okuno T , Yamamoto M , Pasterkamp RJ , Takegahara N , Takamatsu H , Kitao T , Takagi J , Rennert PD , Kolodkin AL , Kumanogoh A , Kikutani H . Semaphorin 7A initiates T-cell-mediated inflammatory responses through alpha1beta1 integrin. Nature 2007; 446(7136): 680–684

[26] You T , Zhu Z , Zheng X , Zeng N , Hu S , Liu Y , Ren L , Lu Q , Tang C , Ruan C , Zhang Y , Zhu L . Serum semaphorin 7A is associated with the risk of acute atherothrombotic stroke. J Cell Mol Med 2019; 23(4): 2901–2906

[27] Lyu X , Liu X , Gong H , Liu Y , Zhou Z , Hu M , Zhang X . Serum Sema7A is increased in patients with acute aortic dissection. Expert Rev Mol Diagn 2023; 23(11): 1027–1035

[28] Li M , Wu L , Wen Y , Wang A , Zhou X , Ren L , Lu Q , Li F , Zhu L , Tang C . Dysregulated cholesterol uptake and efflux of bone marrow-derived alpha-SMA⁺ macrophages contribute to atherosclerotic plaque formation. Cell Mol Life Sci 2025; 82(1): 134

[29] Nakamura R , Sene A , Santeford A , Gdoura A , Kubota S , Zapata N , Apte RS . IL10-driven STAT3 signalling in senescent macrophages promotes pathological eye angiogenesis. Nat Commun 2015; 6(1): 7847

[30] Schirmer SH , Fledderus JO , van der Laan AM , van der Pouw-Kraan TC , Moerland PD , Volger OL , Baggen JM , Bohm M , Piek JJ , Horrevoets AJ , van Royen N . Suppression of inflammatory signaling in monocytes from patients with coronary artery disease. J Mol Cell Cardiol 2009; 46(2): 177–185

[31] Tamagnone L , Artigiani S , Chen H , He Z , Ming GI , Song H , Chedotal A , Winberg ML , Goodman CS , Poo M , Tessier-Lavigne M , Comoglio PM . Plexins are a large family of receptors for transmembrane, secreted, and GPI-anchored semaphorins in vertebrates. Cell 1999; 99(1): 71–80

[32] Tóth E , Erdodi F , Kiss A . Myosin phosphatase is implicated in the control of THP-1 monocyte to macrophage differentiation. Int J Mol Sci 2021; 22(5): 2516

[33] Peng H , Sun F , Jiang Y , Guo Z , Liu X , Zuo A , Lu D . Semaphorin 7a aggravates TGF-beta1-induced airway EMT through the FAK/ERK1/2 signaling pathway in asthma. Front Immunol 2023; 14: 1167605

[34] Körner A , Bernard A , Fitzgerald JC , Alarcon-Barrera JC , Kostidis S , Kaussen T , Giera M , Mirakaj V . Sema7A is crucial for resolution of severe inflammation. Proc Natl Acad Sci USA 2021; 118(9): e2017527118

[35] Wu X , Meng Y , Wang C , Yue Y , Dong C , Xiong S . Semaphorin7A aggravates coxsackievirusB3-induced viral myocarditis by increasing alpha1beta1-integrin macrophages and subsequent enhanced inflammatory response. J Mol Cell Cardiol 2018; 114: 48–57

[36] Parkash J , Messina A , Langlet F , Cimino I , Loyens A , Mazur D , Gallet S , Balland E , Malone SA , Pralong F , Cagnoni G , Schellino R , De Marchis S , Mazzone M , Pasterkamp RJ , Tamagnone L , Prevot V , Giacobini P . Semaphorin7A regulates neuroglial plasticity in the adult hypothalamic median eminence. Nat Commun 2015; 6(1): 6385

[37] Huntington KE , Carlsen L , So EY , Piesche M , Liang O , El-Deiry WS . Integrin/TGF-beta1 inhibitor GLPG-0187 blocks SARS-CoV-2 Delta and Omicron pseudovirus infection of airway epithelial cells in vitro, which could attenuate disease severity. Pharmaceuticals (Basel) 2022; 15(5): 618

[38] MacDonald WJ , Verschleiser B , Carlsen L , Huntington KE , Zhou L , El-Deiry WS . Broad spectrum integrin inhibitor GLPG-0187 bypasses immune evasion in colorectal cancer by TGF-beta signaling mediated downregulation of PD-L1. Am J Cancer Res 2023; 13(7): 2938–2947

RIGHTS & PERMISSIONS

Higher Education Press