Circulating IL-6 upregulates IL-10 production in splenic CD4+ T cells and limits acute kidney injury–induced lung inflammation

Andrés-Hernando, Ana; Okamura, Koji; Bhargava, Rhea; Kiekhaefer, Carol M.; Soranno, Danielle E.; Kirkbride-Romeo, Lara; Gil, Hyo‐Wook; Altmann, Chris; Faubel, Sarah

doi:10.1016/j.kint.2016.12.014

Cited by 43 publications

(18 citation statements)

References 36 publications

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“…In murine kidney ischemia and reperfusion injury, anti-IL-6 therapy by gene delivery was capable of improving renal function and of decreasing NGAL concentrations, indicating some causal involvement of IL-6 (33). IL-6 also seems to have anti-inflammatory effects via upregulation of splenic IL-10 and thereby inhibiting AKI-induced remote organ injury such as lung inflammation (34). Here, we report that IL-6 was able to induce TNK1 expression in a kidney cell line, which so far has been barely found to be regulated.…”

Section: Discussionmentioning

confidence: 71%

Thirty-Eight-Negative Kinase 1 Is a Mediator of Acute Kidney Injury in Experimental and Clinical Traumatic Hemorrhagic Shock

et al. 2020

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Trauma represents a major socioeconomic burden worldwide. After a severe injury, hemorrhagic shock (HS) as a frequent concomitant aspect is a central driver of systemic inflammation and organ damage. The kidney is often strongly affected by traumatic-HS, and acute kidney injury (AKI) poses the patient at great risk for adverse outcome. Recently, thirty-eight-negative kinase 1 (TNK1) was proposed to play a detrimental role in organ damage after trauma/HS. Therefore, we aimed to assess the role of TNK1 in HS-induced kidney injury in a murine and a post hoc analysis of a non-human primate model of HS comparable to the clinical situation. Mice and non-human primates underwent resuscitated HS at 30 mmHg for 60 min. 5 h after the induction of shock, animals were assessed for systemic inflammation and TNK1 expression in the kidney. In vitro, murine distal convoluted tubule cells were stimulated with inflammatory mediators to gain mechanistic insights into the role of TNK1 in kidney dysfunction. In a translational approach, we investigated blood drawn from either healthy volunteers or severely injured patients at different time points after trauma (from arrival at the emergency room and at fixed time intervals until 10 days post injury; identifier: NCT02682550, https://clinicaltrials.gov/ct2/show/NCT02682550). A pronounced inflammatory response, as seen by increased IL-6 plasma levels as well as early signs of AKI, were observed in mice, non-human primates, and humans after trauma/HS. TNK1 was found in the plasma early after trauma-HS in trauma patients. Renal TNK1 expression was significantly increased in mice and non-human primates after HS, and these effects with concomitant induction of apoptosis were blocked by therapeutic inhibition of complement C3 activation in non-human primates. Mechanistically, in vitro data suggested that IL-6 rather than C3 cleavage products

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Section: Discussionmentioning

confidence: 71%

Thirty-Eight-Negative Kinase 1 Is a Mediator of Acute Kidney Injury in Experimental and Clinical Traumatic Hemorrhagic Shock

et al. 2020

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“…Describing this early immune response pathway could have an important impact on future research, including the development of novel therapeutic interventions. Current data suggest that T cells play a key role in the initiation and propagation of the immune reaction in experimental AKI [ 7 , 8 ].…”

Section: Introductionmentioning

confidence: 99%

Postoperative cellular stress in the kidney is associated with an early systemic γδ T-cell immune cell response

Göcze

Ehehalt²,

Zeman³

et al. 2018

Crit Care

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BackgroundBasic science data suggest that acute kidney injury (AKI) induced by ischemia-reperfusion injury (IRI) is an inflammatory process involving the adaptive immune response. Little is known about the T-cell contribution in the very early phase, so we investigated if tubular cellular stress expressed by elevated cell cycle biomarkers is associated with early changes in circulating T-cell subsets, applying a bedside-to-bench approach.MethodsOur observational pilot study included 20 consecutive patients undergoing endovascular aortic repair for aortic aneurysms affecting the renal arteries, thereby requiring brief kidney hypoperfusion and reperfusion. Clinical-grade flow cytometry-based immune monitoring of peripheral immune cell populations was conducted perioperatively and linked to tubular cell stress biomarkers ([TIMP-2]•[IGFBP7]) immediately after surgery. To confirm clinical results and prove T-cell infiltration in the kidney, we simulated tubular cellular injury in an established mouse model of mild renal IRI.ResultsA significant correlation between tubular cell injury and a peripheral decline of γδ T cells, but no other T-cell subpopulation, was discovered within the first 24 hours (r = 0.53; p = 0.022). Turning to a mouse model of kidney warm IRI, a similar decrease in circulating γδ T cells was found and concomitantly was associated with a 6.65-fold increase in γδ T cells (p = 0.002) in the kidney tissue without alterations in other T-cell subsets, consistent with our human data. In search of a mechanistic driver of IRI, we found that the damage-associated molecule high-mobility group box 1 protein HMGB1 was significantly elevated in the peripheral blood of clinical study subjects after tubular cell injury (p = 0.019). Correspondingly, HMGB1 RNA content was significantly elevated in the murine kidney.ConclusionsOur investigation supports a hypothesis that γδ T cells are important in the very early phase of human AKI and should be considered when designing clinical trials aimed at preventing kidney damage.Trial registrationClinicalTrials.gov, NCT01915446. Registered on 5 Aug 2013.Electronic supplementary materialThe online version of this article (10.1186/s13054-018-2094-x) contains supplementary material, which is available to authorized users.

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“…IL-6 is considered to be a primarily pro-inflammatory and IL-10 an anti-inflammatory cytokine [18]. However, IL-6 is also known to be able to promote proand anti-inflammatory responses depending on the type of injury and the organ in which it is examined, e.g., by directly increasing IL-10 levels [19]. It is also known that lidocaine, another common amide-linked local anesthetic, might be able to decrease the release of pulmonary TNF-α and IL-1β after an inflammatory stimulus, while at the same time leaving the secretion of IL-6 unaffected [20].…”

Section: Discussionmentioning

confidence: 99%

The Amide Local Anesthetic Ropivacaine Attenuates Acute Rejection After Allogeneic Mouse Lung Transplantation

Maeyashiki

Jang

Janker

et al. 2019

Lung

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Purpose Acute allograft rejection after lung transplantation remains an unsolved hurdle. The pathogenesis includes an inflammatory response during and after transplantation. Ropivacaine, an amide-linked local anesthetic, has been shown to attenuate lung injury due to its anti-inflammatory effects. We hypothesized that the drug would also be able to attenuate acute rejection (AR) after allogeneic lung transplantation. Methods Allogeneic, orthotopic, single left lung transplantation was performed between BALB/c (donors) and C57BL/6 (recipients) mice. Prior to explantation, lungs were flushed with normal saline with or without ropivacaine (final concentration 1 µM). Plasma levels of tumor necrosis factor-α and interleukins − 6 and − 10 were measured 3 h after transplantation by ELISA. Lung function was assessed on postoperative day five and transplanted lungs were analyzed using histology (AR), immunohistochemistry (infiltrating leukocytes) and Western blot (phosphorylation and expression of Src and caveolin-1). Results Ropivacaine pre-treatment significantly reduced AR scores (median 3 [minimum-maximum 2-4] for control vs. 2 [1-2] for ropivacaine, p < 0.001) and plasma levels of tumor necrosis factor-α (p = 0.01) compared to control, whereas plasma concentrations of interleukin − 6 (p = 0.008) and − 10 (p < 0.001) were increased by ropivacaine. The number of T-lymphocytes infiltrating the transplanted lung was attenuated (p = 0.02), while no differences in macrophage or B-lymphocyte numbers could be observed after ropivacaine pre-treatment. Caveolin-1 phosphorylation in ropivacaine-treated lungs was diminished (p = 0.004). Conclusions Pre-treatment of donor lungs with the local anesthetic ropivacaine diminished histological signs of AR after orthotopic left lung transplantation in mice, most likely due to reduced infiltration of T-lymphocytes into the graft.

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Circulating IL-6 upregulates IL-10 production in splenic CD4+ T cells and limits acute kidney injury–induced lung inflammation

Cited by 43 publications

References 36 publications

Thirty-Eight-Negative Kinase 1 Is a Mediator of Acute Kidney Injury in Experimental and Clinical Traumatic Hemorrhagic Shock

Thirty-Eight-Negative Kinase 1 Is a Mediator of Acute Kidney Injury in Experimental and Clinical Traumatic Hemorrhagic Shock

Postoperative cellular stress in the kidney is associated with an early systemic γδ T-cell immune cell response

The Amide Local Anesthetic Ropivacaine Attenuates Acute Rejection After Allogeneic Mouse Lung Transplantation

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