Small Extracellular Vesicles Propagate the Inflammatory Response After Trauma

Seibold, Tanja; Schönfelder, Jonathan; Weeber, Florian; Lechel, André; Armacki, Milena; Waldenmaier, Mareike; Wille, Christoph; Palmer, Annette; Halbgebauer, Rebecca; Karasu, Ebru; Huber‐Lang, Markus; Kalbitz, Miriam; Radermacher, Peter; Paschke, Stephan; Seufferlein, Thomas; Eiseler, Tim

doi:10.1002/advs.202102381

Cited by 17 publications

(33 citation statements)

References 114 publications

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“…Since it has been shown that EVs are involved in multisystemic signaling mediating regeneration and long-term adaptive responses [ 40 , 41 ], based on our findings as well, it is reasonable to assume that SIRT of the liver could have systemic implications on the immune system. In a recent study, a decrease in CD4 and CD8 carrying EVs was demonstrated, while the number of CD69 carrying EVs in the circulation of CCA patients was increased compared to HVs.…”

Section: Discussionsupporting

confidence: 57%

Selective Internal Radiotherapy Changes the Immune Profiles of Extracellular Vesicles and Their Immune Origin in Patients with Inoperable Cholangiocarcinoma

Haag

Manikkam

Kraft

et al. 2022

Cells

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The incidence of cholangiocellular carcinoma (CCA) is rising worldwide. As there are no specific early symptoms or specific markers of CCA, it is often diagnosed in later inoperable stages. Accumulating evidence underlines the importance of radiation therapy in the induction of antitumor immunity. The surface protein composition on extracellular vesicles (EVs) relates to originating cells and thus may play a role in vesicle function. We assessed immune profiles of EVs and their immune origin in patients with inoperable CCA prior and after selective internal radiotherapy (SIRT). A total of 47 CCA patients receiving SIRT and 12 healthy volunteers (HV) were included. Blood was withdrawn before therapy (pre T) and after T. EVs were purified from plasma by cluster of differentiation (CD)9-, CD63-, and CD81-immunobead isolation. To detect differently abundant surface markers, dynamic range and EVs input quality were assessed. A total of 37 EVs surface markers were measured by flow cytometry and correlated either with the administered activity dose (MBq) or with the interval until death (month). EVs phenotyping identified lymphocytes, B cells, NK cells, platelets, endothelial cells, leukocyte activation, B cell activation, T and B cell adhesion markers, stem/progenitor cells, and antigen-presenting cells (APC) as EVs-parenteral cells. CD4 and CD8 significantly declined, while other markers significantly increased in CCA patients pre T vs. HV. Platelets-deriving EVs significantly decreased, normalizing to levels of HV but still significantly increasing vs. HV post SIRT. B cells-deriving EVs significantly increased pre T vs. HV, positively correlating with administered activity dose. MHCII and CD40 EVs significantly increased pre SIRT and negatively correlated with administered activity dose, while EVs from antigen presenting cells and CD49e pre SIRT positively correlated with survival time after therapy. Increased levels of CD24 and CD44 in cancer pre T were significantly decreased post T. Among the heterogeneity of EVs that was demonstrated, in particular, B cells-deriving, MHCII, and CD40 positive or APC-deriving EVs need to be further studied for their diagnostic or prognostic relevance in clinical scenarios.

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Section: Discussionsupporting

confidence: 57%

Selective Internal Radiotherapy Changes the Immune Profiles of Extracellular Vesicles and Their Immune Origin in Patients with Inoperable Cholangiocarcinoma

Haag

Manikkam

Kraft

et al. 2022

Cells

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“…TxT experiments were conducted by inducing a defined bilateral lung contusion using an air pressure blast wave on anesthetized 12-week old male C57BL/6 animals (14). The level of pulmonary contusion was chosen based on histologic, cardiopulmonary as well as immunologic changes in earlier studies and was sufficient to induce a profound local and systemic inflammatory response, but without being lethal itself (16).…”

Section: Thorax Trauma Polytrauma As Well As Polytrauma With Hemorrha...mentioning

confidence: 99%

Endothelial Protein kinase D1 is a major regulator of post-traumatic hyperinflammation

Schönfelder

Seibold²,

Morawe³

et al. 2023

Front. Immunol.

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Trauma is a major cause of death worldwide. The post-traumatic immune response culminates in the release of pro-inflammatory mediators, translating in the infiltration of neutrophils (PMNs) at injury sites. The extent of this inflammation is determined by multiple factors, such as PMN adhesion to the endothelium, transendothelial migration, endothelial barrier integrity as well as PMN swarming, mass infiltration and activation. This process is initiated by secondary lipid mediators, such as leukotriene B4 (LTB4). We here provide evidence that Protein kinase D1 (PRKD1) in endothelial cells is implicated in all these processes. Endothelial PRKD1 is activated by pro-inflammatory stimuli and amplifies PMN-mediated inflammation by upregulation of cytokine and chemokines as well as adhesion molecules, such as ICAM-1, VCAM-1 and E-selectin. This induces enhanced PMN adhesion and trans-migration. PRKD1 activation also destabilizes endothelial VE-cadherin adhesion complexes and thus the endothelial barrier, fostering PMN infiltration. We even describe a yet unrecognized PRKD1-dependant mechanism to induce biosynthesis of the PMN-swarming mediator LTB4 directed via intercellular communication through small extracellular vesicles (sEVs) and enhanced CXCL8 secretion from activated endothelial cells. These endothelial sEVs transfer the LTB4 biosynthesis enzyme LTA4 hydrolase (LTA4H) to prime PMNs, while initiating biosynthesis also requires additional signals, like CXCL8. We further demonstrate the respective LTA4H-positive sEVs in the serum of polytrauma patients, peaking 12 h post injury. Therefore, PRKD1 is a key regulator in the coordinated communication of the endothelium with PMNs and a vital signaling node during post-traumatic inflammation.

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“…Moreover, Seibold et al suggested that extracellular vesicles secreted on thorax trauma are strongly associated with sepsis and biochemical markers of AKI (110). The authors further showed the thorax trauma–responding extracellular vesicles might originate from endothelial cells and contain endothelial activators, such as vascular cell adhesion molecule 1, E‐selectin, and cytokines (110). In contrast, there is some evidence for therapeutic roles of extracellular vesicles during sepsis-associated AKI.…”

Section: Inflammationmentioning

confidence: 99%

The Pathophysiology of Sepsis-Associated AKI

Kuwabara

Goggins

Okusa

2022

CJASN

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Sepsis-associated AKI is a life-threatening complication that is associated with high morbidity and mortality in patients who are critically ill. Although it is clear early supportive interventions in sepsis reduce mortality, it is less clear that they prevent or ameliorate sepsis-associated AKI. This is likely because specific mechanisms underlying AKI attributable to sepsis are not fully understood. Understanding these mechanisms will form the foundation for the development of strategies for early diagnosis and treatment of sepsis-associated AKI. Here, we summarize recent laboratory and clinical studies, focusing on critical factors in the pathophysiology of sepsis-associated AKI: microcirculatory dysfunction, inflammation, NOD-like receptor protein 3 inflammasome, microRNAs, extracellular vesicles, autophagy and efferocytosis, inflammatory reflex pathway, vitamin D, and metabolic reprogramming. Lastly, identifying these molecular targets and defining clinical subphenotypes will permit precision approaches in the prevention and treatment of sepsis-associated AKI.

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Small Extracellular Vesicles Propagate the Inflammatory Response After Trauma

Cited by 17 publications

References 114 publications

Selective Internal Radiotherapy Changes the Immune Profiles of Extracellular Vesicles and Their Immune Origin in Patients with Inoperable Cholangiocarcinoma

Selective Internal Radiotherapy Changes the Immune Profiles of Extracellular Vesicles and Their Immune Origin in Patients with Inoperable Cholangiocarcinoma

Endothelial Protein kinase D1 is a major regulator of post-traumatic hyperinflammation

The Pathophysiology of Sepsis-Associated AKI

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