Angiotensin 1–7, but not the thrombin-cleaved osteopontin C-terminal fragment, attenuates osteopontin-mediated macrophage-induced endothelial-cell inflammation

Hamias, Rachel; Rudich, Assaf; Greenberg, George; Szendro, Gabriel; Wolak, Talya

doi:10.1007/s00011-017-1120-9

Cited by 5 publications

(3 citation statements)

References 40 publications

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“…Recent studies have found that the MMP-3 or 7 cleavage of OPN-C fragments results has aα9β1 binding site, which facilitates its role in the development of inflammatory arthritis [ 50 ]. Another study has shown that OPN-C promotes inflammation by the activation of the NF-κB pathway [ 51 ]. We found that OPN-WT and cleaved forms of OPN coexisted in the ipsilateral cortex following HI injury in neonatal mice, and the C-terminal domain of OPN was the molecular basis for the direct binding between OPN and GAL-3.…”

Section: Discussionmentioning

confidence: 99%

Mechanistic Insights into the Role of OPN in Mediating Brain Damage via Triggering Lysosomal Damage in Microglia/Macrophage

Gai

Zhao

Xin

et al. 2023

Cells

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We previously found that osteopontin (OPN) played a role in hypoxia–ischemia (HI) brain damage. However, its underlying mechanism is still unknown. Bioinformatics analysis revealed that the OPN protein was linked to the lysosomal cathepsin B (CTSB) and galectin-3 (GAL-3) proteins after HI exposure. In the present study, we tested the hypothesis that OPN was able to play a critical role in the lysosomal damage of microglia/macrophages following HI insult in neonatal mice. The results showed that OPN expression was enhanced, especially in microglia/macrophages, and colocalized with lysosomal-associated membrane protein 1 (LAMP1) and GAL-3; this was accompanied by increased LAMP1 and GAL-3 expression, CTSB leakage, as well as impairment of autophagic flux in the early stage of the HI process. In addition, the knockdown of OPN expression markedly restored lysosomal function with significant improvements in the autophagic flux after HI insult. Interestingly, cleavage of OPN was observed in the ipsilateral cortex following HI. The wild-type OPN and C-terminal OPN (Leu152-Asn294), rather than N-terminal OPN (Met1-Gly151), interacted with GAL-3 to induce lysosomal damage. Furthermore, the secreted OPN stimulated lysosomal damage by binding to CD44 in microglia in vitro. Collectively, this study demonstrated that upregulated OPN in microglia/macrophages and its cleavage product was able to interact with GAL-3, and secreted OPN combined with CD44, leading to lysosomal damage and exacerbating autophagosome accumulation after HI exposure.

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Section: Discussionmentioning

confidence: 99%

Mechanistic Insights into the Role of OPN in Mediating Brain Damage via Triggering Lysosomal Damage in Microglia/Macrophage

Gai

Zhao

Xin

et al. 2023

Cells

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“…The macrophages which were recruited to the site of injury released a variety of proinflammatory cytokines such as interleukin-1 β (IL-1 β ) and tumor necrosis factor α (TNF- α ) [16], which had the functions of removing cell debris and apoptotic bodies [1], phagocytizing necrotic substances, releasing CCL2, CX3CL1, and other chemokines [17], and promoting muscle healing [18] and immune cell infiltration [19]. Stimulation of macrophages could induce endothelial cell inflammatory response [20].…”

Section: Discussionmentioning

confidence: 99%

Role of p120 Catenin in Epac1-Induced Chronic Postsurgical Pain in Rats

Pan

Huang

Shen

et al. 2019

Pain Research and Management

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Chronic postsurgical pain (CPSP) is a chronic pain state that is difficult to be treated clinically. A series of complicated changes have been produced from nociceptive stimulation to the occurrence and development of postsurgical pain. Many mechanisms remain unclear. In order to study the role of intercellular gap junctions in inducing inflammatory microenvironment at the beginning of nociceptor after operation, the model of skin/muscle incision and retraction (SMIR) was established. We observed the changes of the expression of exchange proteins directly activated by cAMP-1 (Epac1) and p120 catenin (p120), the quantities of macrophages and endothelial cells, vascular endothelial permeability, and mechanical withdrawal threshold (MWT). It was found that macrophages and endothelial cells were functionally coupled through Epac1-p120. Adhesive linkage disorder remodeled the chronic, inflammatory, and eutrophic microenvironment at the beginning of nociceptor after operation through macrophages, endothelial cells, and endothelial paracellular pathways. It might be an early event and a key step in peripheral sensitization of CPSP. The expression of p120 in muscle tissue around the incision might become a prognostic marker for the conversion of acute postsurgical pain into CPSP. Targeted intervention of Epac1-p120 might be a clinical strategy for inhibiting the conversion of acute postsurgical pain into CPSP.

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“…This sequence is disrupted following thrombin cleavage, but the loss of the pro-chemotactic activity in intact OPN is compensated for by the released OPN-CTF, which acquires a new conformation-dependent chemotactic activity towards DC [ 194 ]. Activity of OPN-CTF was confirmed in a human macrophage cell line (U937) where OPN-CTF was not as pro-inflammatory as OPN-FL and OPN-R [ 195 ]. Thus, thrombin cleavage of OPN occurs in vivo, and proteolysis regulates the functions of OPN with both generated fragments, OPN-R and OPN-CTF, acquiring different properties than possessed by OPN-FL.…”

Section: Protease Cleavages Of Opnmentioning

confidence: 99%

Thrombin Cleavage of Osteopontin and the Host Anti-Tumor Immune Response

Leung

Myles

Morser

2023

Cancers

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Osteopontin (OPN) is a multi-functional protein that is involved in various cellular processes such as cell adhesion, migration, and signaling. There is a single conserved thrombin cleavage site in OPN that, when cleaved, yields two fragments with different properties from full-length OPN. In cancer, OPN has tumor-promoting activity and plays a role in tumor growth and metastasis. High levels of OPN expression in cancer cells and tumor tissue are found in various types of cancer, including breast, lung, prostate, ovarian, colorectal, and pancreatic cancer, and are associated with poor prognosis and decreased survival rates. OPN promotes tumor progression and invasion by stimulating cell proliferation and angiogenesis and also facilitates the metastasis of cancer cells to other parts of the body by promoting cell adhesion and migration. Furthermore, OPN contributes to immune evasion by inhibiting the activity of immune cells. Thrombin cleavage of OPN initiates OPN’s tumor-promoting activity, and thrombin cleavage fragments of OPN down-regulate the host immune anti-tumor response.

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Angiotensin 1–7, but not the thrombin-cleaved osteopontin C-terminal fragment, attenuates osteopontin-mediated macrophage-induced endothelial-cell inflammation

Abstract: OPN-C induces lower macrophage-induced endothelial inflammation compared to OPN-FL or OPN-N, but unlike angiotensin 1-7, fails to prevent endothelial inflammation induced by subsequent pro-inflammatory macrophage stimulation.

Cited by 5 publications

References 40 publications

Mechanistic Insights into the Role of OPN in Mediating Brain Damage via Triggering Lysosomal Damage in Microglia/Macrophage

Mechanistic Insights into the Role of OPN in Mediating Brain Damage via Triggering Lysosomal Damage in Microglia/Macrophage

Role of p120 Catenin in Epac1-Induced Chronic Postsurgical Pain in Rats

Thrombin Cleavage of Osteopontin and the Host Anti-Tumor Immune Response

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