Opinion: Endothelial Cells - Macrophage-Like Gatekeepers?

Stolarz, Amanda J.; Mu, Shengyu; Zhang, Huiliang; Fouda, Abdelrahman Y.; Rusch, Nancy J.; Ding, Zufeng

doi:10.3389/fimmu.2022.902945

Cited by 13 publications

(15 citation statements)

References 27 publications

(44 reference statements)

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“…ECs are the central and active players in the immune system and vasculature ( 6 ). Although ECs are not professional immune cells, they essentially execute immune functions by sensing and responding to inflammatory cytokines, viral and bacterial infection ( 7 ). Upon inflammation, ECs recruit immune cells, such as neutrophils and monocytes and direct the extravasation of leukocytes at the inflammatory site through inducing the adhesion molecules like vascular cell adhesion molecule 1 (VCAM1) or intercellular adhesion molecule 1 (ICAM1) and E-selectin (SELE) expression ( 8 ).…”

Section: Introductionmentioning

confidence: 99%

PHACTR1, a coronary artery disease risk gene, mediates endothelial dysfunction

et al. 2022

Front. Immunol.

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Genome-wide association studies (GWAS) have recently identified phosphatase and actin regulator-1 (PHACTR1) as a critical risk gene associated with polyvascular diseases. However, it remains largely unclear how PHACTR1 is involved in endothelial dysfunction. Here, by mining published datasets of human stable and vulnerable/ruptured plaque tissues, we observed upregulated expression of PHACTR1 in vulnerable/ruptured plaques. Congruent with these data, we demonstrated increased Phactr1 gene expression in aortic endothelium from ApoE-/- mice fed a western type diet compared with that in normal C57BL/6J mice. Relevantly, PHACTR1 gene expression was upregulated by pro-inflammatory and pro-atherogenic stimuli, including TNF-α, IL-1β and oxidized LDL (oxLDL). By employing next-generation RNA sequencing, we demonstrate that PHACTR1 overexpression disrupts pathways associated with endothelial homeostasis. Cell biological studies unravel that PHACTR1 mediates endothelial inflammation and monocyte adhesion by activating NF-κB dependent intercellular adhesion molecule 1 (ICAM1) and vascular cell adhesion molecule 1 (VCAM1) expression. In addition, overexpression of PHACTR1 also reduces the generation of nitric oxide (NO) by inhibiting Akt/eNOS activation. In-house compound screening of vasoprotective drugs identifies several drugs, including lipid-lowering statins, decreases PHACTR1 gene expression. However, PHACTR1 gene expression was not affected by another lipid-lowering drug-fenofibrate. We also performed a proteomic study to reveal PHACTR1 interacting proteins and validated that PHACTR1 can interact with heat shock protein A8 (HSPA8) which was reported to be associated with coronary artery disease and eNOS degradation. Further studies are warranted to confirm the precise mechanism of PHACTR1 in driving endothelial dysfunction. In conclusion, by using systems biology approach and molecular validation, we disclose the deleterious effects of PHACTR1 on endothelial function by inducing endothelial inflammation and reducing NO production, highlighting the potential to prevent endothelial dysfunction and atherosclerosis by targeting PHACTR1 expression. The precise role of endothelial cell PHACTR1 in polyvascular diseases remains to be validated in diseased conditions.

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Section: Introductionmentioning

confidence: 99%

PHACTR1, a coronary artery disease risk gene, mediates endothelial dysfunction

et al. 2022

Front. Immunol.

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“…ECs are sensitive to different stimuli, including low oxygen levels, nutrient availability, oxidative stress, and unfolded proteins. Hypoxia and nutrient deprivation represent common stressful features of the vascular microenvironment that may activate ECs [ 20 ]. In such cases, after vascular reperfusion and restoration of physiological levels of oxygen and nutrients, ECs may return to the quiescent state [ 20 ].…”

Section: Autophagy In the Main Cellular Types Involved In Dental Impl...mentioning

confidence: 99%

“…Generally, ECs are not regarded as classic immune cells; however, they express a variety of innate immune receptors such as NOD-like receptors (NLRs) and Toll-like receptors (TLRs). These receptors activate intracellular inflammatory pathways mediated by nuclear factor kappa B (NF-κB) and the mitogen-activated protein kinases [ 20 ]. Interestingly, MFs and ECs have similar evolutionarily conserved mechanisms of defense, such as autophagy and phagocytosis [ 20 , 43 ].…”

Section: Autophagy In the Main Cellular Types Involved In Dental Impl...mentioning

confidence: 99%

“…These receptors activate intracellular inflammatory pathways mediated by nuclear factor kappa B (NF-κB) and the mitogen-activated protein kinases [ 20 ]. Interestingly, MFs and ECs have similar evolutionarily conserved mechanisms of defense, such as autophagy and phagocytosis [ 20 , 43 ]. MFs are phagocytes highly specialized in the detection and removal of apoptotic cells, cell debris, and pathogens.…”

Section: Autophagy In the Main Cellular Types Involved In Dental Impl...mentioning

confidence: 99%

“…MFs are phagocytes highly specialized in the detection and removal of apoptotic cells, cell debris, and pathogens. In turn, ECs are able to adopt MFs-like functions (that may include phagocytosis, autophagy, and the innate immune response) in order to protect the underlying tissue against blood-generated toxins and pathogens [ 20 , 77 ]; however, the precise mechanisms of ECs MFs-like function are still a mystery [ 20 , 77 ]. Recently, the importance of ECs autophagy, especially in the context of oral post-implant surgery wound healing, has been increasingly recognized; however, ECs autophagy remains a poorly explored field, but surely full of promises, particularly regarding oral implantology ( Figure 3 a).…”

Section: Autophagy In the Main Cellular Types Involved In Dental Impl...mentioning

confidence: 99%

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Autophagy Plays Multiple Roles in the Soft-Tissue Healing and Osseointegration in Dental Implant Surgery—A Narrative Review

et al. 2022

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Dental endo-osseous implants have become a widely used treatment for replacing missing teeth. Dental implants are placed into a surgically created osteotomy in alveolar bone, the healing of the soft tissue lesion and the osseointegration of the implant being key elements to long-term success. Autophagy is considered the major intracellular degradation system, playing important roles in various cellular processes involved in dental implant integration. The aim of this review is an exploration of autophagy roles in the main cell types involved in the healing and remodeling of soft tissue lesions and implant osseointegration, post-implant surgery. We have focused on the autophagy pathway in macrophages, endothelial cells; osteoclasts, osteoblasts; fibroblasts, myofibroblasts and keratinocytes. In macrophages, autophagy modulates innate and adaptive immune responses playing a key role in osteo-immunity. Autophagy induction in endothelial cells promotes apoptosis resistance, cell survival, and protection against oxidative stress damage. The autophagic machinery is also involved in transporting stromal vesicles containing mineralization-related factors to the extracellular matrix and regulating osteoblasts’ functions. Alveolar bone remodeling is achieved by immune cells differentiation into osteoclasts; autophagy plays an important and active role in this process. Autophagy downregulation in fibroblasts induces apoptosis, leading to better wound healing by improving excessive deposition of extracellular matrix and inhibiting fibrosis progression. Autophagy seems to be a dual actor on the scene of dental implant surgery, imposing further research in order to completely reveal its positive features which may be essential for clinical efficacy.

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Immunomodulation of wound healing leading to efferocytosis

Zhao,

Li,

Mao

et al. 2024

Smart Medicine

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Effectively eliminating apoptotic cells is precisely controlled by a variety of signaling molecules and a phagocytic effect known as efferocytosis. Abnormalities in efferocytosis may bring about the development of chronic conditions, including angiocardiopathy, chronic inflammatory diseases and autoimmune diseases. During wound healing, failure of efferocytosis leads to the collection of apoptosis, the release of necrotic material and chronic wounds that are difficult to heal. In addition to the traditional phagocytes‐macrophages, other important cell species including dendritic cells, neutrophils, vascular endothelial cells, fibroblasts and keratinocytes contribute to wounding healing. This review summarizes how efferocytosis‐mediated immunomodulation plays a repair‐promoting role in wound healing, providing new insights for patients suffering from various cutaneous wounds.

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Opinion: Endothelial Cells - Macrophage-Like Gatekeepers?

Cited by 13 publications

References 27 publications

PHACTR1, a coronary artery disease risk gene, mediates endothelial dysfunction

PHACTR1, a coronary artery disease risk gene, mediates endothelial dysfunction

Autophagy Plays Multiple Roles in the Soft-Tissue Healing and Osseointegration in Dental Implant Surgery—A Narrative Review

Immunomodulation of wound healing leading to efferocytosis

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