Phosphatidylserine-dependent ingestion of apoptotic cells promotes TGF-β1 secretion and the resolution of inflammation

Huynh, Mai-Lan N.; Fadok, Valerie A.; Henson, Peter M.

doi:10.1172/jci11638

Cited by 506 publications

(375 citation statements)

References 51 publications

(33 reference statements)

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“…This enzyme selectively cleaves DNA at sites located between nucleosomal units generating mono- and oligonucleosomal DNA fragments. In the final stage of apoptosis, the cell disintegrates into apoptotic bodies that are rapidly phagocytosed and destroyed by phagocytes avoiding inflammation, tissue damage, and damage to surrounding cells [36]. …”

Section: Discussionmentioning

confidence: 99%

Cardiorenal Syndrome Type 1: Activation of Dual Apoptotic Pathways

Pastori¹,

Virzì²,

Brocca³

et al. 2015

Cardiorenal Med

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Cardiorenal syndrome type 1 (CRS1) pathophysiology is complex, and immune-mediated damage, including alterations in the immune response with monocyte apoptosis and cytokine release, has been reported as a potential mechanism. In this study, we examined the putative role of renal tubular epithelial cell (RTC) apoptosis as a pathogenic mechanism in CRS1. In particular, we investigated the caspase pathways involved in induced apoptosis. We enrolled 29 patients with acute heart failure (AHF), 11 patients with CRS1, and 15 controls (CTR) without AHF or acute kidney injury (AKI). Patients who had AKI prior to the episode of AHF or who had any other potential causes of AKI were excluded. Plasma from different groups was incubated with RTCs for 24 h. Subsequently, cell apoptosis, DNA fragmentation, and caspase-3, -8, and -9 activities were investigated in RTCs incubated with AHF, CRS1, and CTR plasma. A p value <0.5 was considered statistically significant. A quantitative analysis of apoptosis showed significantly higher apoptosis rates in CRS1 patients compared to AHF patients and CTR (p < 0.01). This increase in apoptosis was strongly confirmed by caspase-3 levels (ρ = 0.73). Caspase-8 and -9 were significantly higher in CRS1 patients compared to AHF patients and CTR (p < 0.01). Furthermore, caspase-3 levels showed a significantly positive correlation with caspase-8 (ρ = 0.57) and -9 (ρ = 0.47; p < 0.001). This study demonstrated the significantly heightened presence of dual apoptotic disequilibrium in CRS1. Our findings indicated that apoptosis may have a central role in the mechanism of CRS1, and it could be a potential therapeutic target in this syndrome.

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Section: Discussionmentioning

confidence: 99%

Cardiorenal Syndrome Type 1: Activation of Dual Apoptotic Pathways

Pastori¹,

Virzì²,

Brocca³

et al. 2015

Cardiorenal Med

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“…Indeed, PS which is well-known for being linked to the anti-inflammatory effects triggered by apoptotic cells [33], interacts with both CRT and C1q. Our previous study suggested that surface CRT level could modulate C1q/PS binding, thus possibly modifying PS recognition by other phagocyte receptors and bridging molecules, and consequently affecting the downstream signaling events.…”

Section: Discussionmentioning

confidence: 99%

Relative Contribution of C1q and Apoptotic Cell-Surface Calreticulin to Macrophage Phagocytosis

Verneret¹,

Tacnet-Delorme²,

Osman³

et al. 2014

J Innate Immun

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C1q has been shown to recognize apoptotic cells, to enhance their uptake and to modulate cytokine release by phagocytes and thus promote immune tolerance. Surface-exposed calreticulin (CRT), known as a C1q receptor, is also considered to be an early eat-me signal that enhances the phagocytosis of apoptotic cells and is capable of eliciting an immunogenic response. However, the molecular mechanisms that trigger these functions are not clear. We hypothesized that CRT and C1q might act together in these processes. We first showed, by means of fluorescence resonance energy transfer (FRET), that CRT interacts with the C1q globular region at the surface of early apoptotic cells. Next, we pointed out that knockdown of CRT on early apoptotic HeLa cells impairs the enhancement effect of C1q on their uptake by THP-1 monocyte-derived macrophages. Furthermore, a deficiency of CRT induces contrasting effects on cytokine release by THP-1 macrophages, increasing interleukin (IL)-6 and monocyte chemotactic protein 1/CCL2 and decreasing IL-8. Remarkably, these effects were greatly reduced when apoptotic cells were opsonized by C1q, which counterbalanced the effect of the CRT deficiency. These results demonstrate that CRT-C1q interaction is involved in the C1q bridging function and they highlight the particular ability of C1q to control the phagocyte inflammatory status, i.e. by integrating the molecular changes that could occur at the surface of dying cells.

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“…During this process level of cytokines related to natural tissue homeostasis such as TGF-β and IL-10 are found to be especially elevated thus naturally facilitating tissue return to functionality after an inflammatory event [28][29] . We administered an average quantity of 6 × 10 8 total PMNC (mainly neutrophils)…”

Section: Discussionmentioning

confidence: 99%

Processing Volumes and Therapeutic Cellular Doses of Point of Care Bone Marrow Concentrates

Rodr韌uez

Seijas

Codinach

et al. 2016

International Journal of Orthopaedics

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formulation of BMC make it difficult to circumscribe basic processing variables to generate them. We analyzed the influence of processing different Bone Marrow (BM) volumes over the formulation and deliverable cell dose of BMC METHODS: Main cellular populations were characterized in BMC manufactured and applied for autologous use during the same surgical procedure. To do this, Flow Cytometry and Fibroblastic Colony Forming Units (CFU-Fs) assays were used. RESULTS: Cell concentration of aspirates was not statistically influenced in the range of volumes analyzed. Consequently the quality of BM seems to be conserved in the range of volumes assayed. By using the protocol described, the quality of BMC traditionally defined as CFU-F per mL did not differ in the range of volumes assayed whereas total dose of CFU-F and other differentiated cells effectively changed. CONCLUSIONS:The volume of BM defines cellular doses arriving to the patient with statistically significant differences. Parameters currently used to describe the quality of BMC as CFU-F/mL appear to be directly influenced by working volumes and thus total cellular doses applied might better characterize these products. Finally, since it is uncertain what cells within BMC form part of its active substance, the quantification of main cell subsets could be helpful to better understand where, when and how these medicinal products work. ABSTRACT AIMS: Bone Marrow Concentrates (BMC) applied to treat several osteo-articular pathologies had reported positive clinical outcomes at short-to medium-term follow up. However, the diversity of indications reported and the lack of consensus describing the ORIGINAL ARTICLE Key words:

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Phosphatidylserine-dependent ingestion of apoptotic cells promotes TGF-β1 secretion and the resolution of inflammation

Cited by 506 publications

References 51 publications

Cardiorenal Syndrome Type 1: Activation of Dual Apoptotic Pathways

Cardiorenal Syndrome Type 1: Activation of Dual Apoptotic Pathways

Relative Contribution of C1q and Apoptotic Cell-Surface Calreticulin to Macrophage Phagocytosis

Processing Volumes and Therapeutic Cellular Doses of Point of Care Bone Marrow Concentrates

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