CD70 limits atherosclerosis and promotes macrophage function

Abstract

The co-stimulatory molecule CD70 is expressed on activated immune cells and is known to modulate responses of T, B, and NK cells via its receptor CD27. Until now, there is only limited data describing the role of CD70 in atherosclerosis. We observed that ruptured human carotid atherosclerotic plaques displayed higher CD70 expression than stable carotid atherosclerotic plaques, and that CD70 expression in murine atheroma localized to macrophages. Lack of CD70 impaired the inflammatory capacity (e. g. reactive oxygen species and nitric oxide production) of bone marrow-derived macrophages, increased both M1-like and M2-like macrophage markers, and rendered macrophages metabolically inactive and prone to apoptosis. Moreover, CD70-deficient macrophages expressed diminished levels of scavenger receptors and ABC-transporters, impairing uptake of oxidised low-density lipoprotein (oxLDL) and cholesterol efflux, respectively. Hyperlipidaemic Apoe mice reconstituted with CD70-deficient bone marrow displayed a profound increase in necrotic core size, plaque area, and number of lesional macrophages as compared to mice receiving control bone marrow. Accordingly, 18 week-old, chow diet-fed CD70-deficient Apoe mice displayed larger atheroma characterised by lower cellularity and more advanced plaque phenotype than Apoe mice. In conclusion, CD70 promotes macrophage function and viability and is crucial for effective phagocytosis and efflux of oxLDL. Deficiency in CD70 results in more advanced atheroma. Our data suggest that CD70 mitigates atherosclerosis at least in part by modulating macrophage function.

Hitting more birds with one stone: CD70 as an actionable immunotherapeutic target in recurrent glioblastoma

“…Other slightly downregulated genes included CDH2 (Cadherin 2), PLAUR, and CXCR4; genes known to be associated with the Mesenchymal subtype in GBM and a worse overall prognosis (Gilder et al 2018;Tao et al 2020;Yi et al 2018). OLIG2, a transcription factor commonly associated with the proneural subtype and tumor recurrence (Bouchart et al 2020, Lu et al 2016, showed upregulation following CD70 knockdown, while expression of the proangiogenic factor VEGFA was depressed, indicating that CD70 may play a role in GBM angiogenesis, a characteristic previously documented in other pathologies, but not in cancer (Simons et al 2018, Winkels et al 2017.…”

Dynamic Macrophages: Understanding Mechanisms of Activation as Guide to Therapy for Atherosclerotic Vascular Disease

“…CD70 promotes macrophage function and viability, and is important for effective efferocytosis and extrusion of oxLDL. CD70 deficiency results in more advanced atheroma ( 85 ). These are just a few of the immune checkpoints that affect macrophage behavior.…”

Metabolism-associated danger signal-induced immune response and reverse immune checkpoint-activated CD40+ monocyte differentiation

“…Evidence for the role of CD27:CD70 in atherosclerosis is conflicting as ruptured atherosclerotic plaques expressed higher CD70 than those in stable lesions [93], and CD70 transgenic mice attenuated atherosclerotic development [94]. …”

“…CD27 + Treg is reduced in myocardial infarction patients, and this subset has high suppressive potential [95]. CD70 deficiency reduced spleen Treg in ApoE −/− mice [93] and CD27 deficiency reduced Treg in solid tumor in mice [96], suggesting that CD27:CD70 may have an immunosuppressive role in atherosclerosis and tumor growth.…”

“…CD70 transgenic mice displayed increased MC apoptosis [94]. CD70 promoted ox-LDL efflux in MØ [93] while engineered anti-CD70 increased MØ phagocytosis and prolonged the survival in lymphoma mice [97]. …”