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TANK prevents IFN-dependent fatal diffuse alveolar hemorrhage by suppressing DNA-cGAS aggregation.

ABSTRACT: Diffuse alveolar hemorrhage (DAH) is one of the serious complications associated with systemic lupus erythematosus, an autoimmune disease whose pathogenesis involves type I IFNs and cytokines. Here, we show that TANK, a negative regulator of the NF-κB signaling via suppression of TRAF6 ubiquitination, is critical for the amelioration of fatal DAH caused by lung vascular endothelial cell death in a mouse model of systemic lupus erythematosus. The development of fatal DAH in the absence of TANK is mediated by type I IFN signaling, but not IL-6. We further uncover that STING, an adaptor essential for the signaling of cytoplasmic DNA sensor cyclic GMP-AMP (cGAMP) synthase (cGAS), plays a critical role in DAH under Tank deficiency. TANK controls cGAS-mediated cGAMP production and suppresses DNA-mediated induction of IFN-stimulated genes in macrophages by inhibiting the formation of DNA-cGAS aggregates containing ubiquitin. Collectively, TANK inhibits the cGAS-dependent recognition of cytoplasmic DNA to prevent fatal DAH in the murine lupus model.

SUBMITTER: Wakabayashi A

PROVIDER: S-EPMC8616552 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature

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TANK prevents IFN-dependent fatal diffuse alveolar hemorrhage by suppressing DNA-cGAS aggregation.

Wakabayashi Atsuko A Yoshinaga Masanori M Takeuchi Osamu O

Life science alliance 20211124 2

Diffuse alveolar hemorrhage (DAH) is one of the serious complications associated with systemic lupus erythematosus, an autoimmune disease whose pathogenesis involves type I IFNs and cytokines. Here, we show that TANK, a negative regulator of the NF-κB signaling via suppression of TRAF6 ubiquitination, is critical for the amelioration of fatal DAH caused by lung vascular endothelial cell death in a mouse model of systemic lupus erythematosus. The development of fatal DAH in the absence of TANK is ...[more]

PMID: 34819357

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Project description:AudienceThis scenario was developed to educate junior and senior emergency medicine (EM) residents.IntroductionEM Model of Practice recommends that the residents are able to manage patients in a critical condition from massive hemoptysis. Mild to moderate hemoptysis can be self-limiting and often can be managed with conservative measures; however, massive hemoptysis is a life-threatening emergency that needs to be managed promptly. Mortality from massive hemoptysis is about 13%-18%.1 There are several causes for hemoptysis ranging from pulmonary to vascular causes. Diffuse alveolar hemorrhage (DAH) causes hemoptysis only 0.2% which makes it a very rare but devastating disease.2 Hemoptysis from DAH can present a significant challenge to an EM physician since it can present in various ways including chest pain, shortness of breath or hemoptysis. Up to 40% of the patients can present without hemoptysis which makes it a diagnostic dilemma.3 Patients presenting with massive hemoptysis from DAH require management for hypovolemic shock, hypoxic respiratory arrest and potential cardiac arrest. The physicians also need to perform adequate ventilator management to help with alveolar recruitment. This simulation case can help discuss some of the nuances of the management of hemoptysis and DAH.ObjectivesBy the end of this simulation session, learners will be able to: (1) recognize worsening respiratory status of a patient with hemoptysis and intervene appropriately, (2) manage a patient with severe hemoptysis and perform appropriate ventilator management, (3) manage sinus tachycardia with QT prolongation on the ECG caused by cocaine and hypomagnesemia, (4) address various etiologies of hemoptysis, (5) discuss the causes of massive hemoptysis and management options, and (6) review ventilation strategies in an intubated hypoxic patient.Educational methodsThis session was conducted using high-fidelity simulation, which was immediately followed by an in-depth debriefing session. Each session had 3 EM residents from various levels of training on the team and 7 observers. There was 1 simulation instructor running the session and 1 simulation technician who acted as a nurse.Research methodsAfter the simulation and debriefing session was complete, an online survey was sent via surveymonkey.com to all the participants. The survey collected responses to the following questions: (1) the case was believable, (2) the case had right amount of complexity, (3) the case helped in improving medical knowledge and patient care, (4) the simulation environment gave me a real-life experience and, (5) the debriefing session after simulation helped improve my knowledge. A Likert scale was used to collect the responses.ResultsSeven learners responded to the survey. One hundred percent of them either agreed or strongly agreed that the case was beneficial in learning and improving patient care. They also agreed that it helped in improving medical knowledge. The post-session debrief was found to be very helpful by all the learners.DiscussionHigh-fidelity simulation was a cost-effective yet realistic way to manage severe hemoptysis, PEA (pulseless electrical activity), and persistent hypoxia in patients with diffuse alveolar hemorrhage. Starting the case with severe hypoxia that quickly progresses to PEA helps the learner to manage the patient quickly and effectively. Overall, learners enjoyed managing the patient, followed by discussing the various management strategies.TopicsHemoptysis, diffuse alveolar hemorrhage, medical simulation, respiratory.

Project description:Diffuse alveolar hemorrhage after hematopoietic stem cell transplantation is a frequently fatal complication with no standard therapy. Although significant changes in supportive and intensive care measures for patients undergoing hematopoietic stem cell transplantation have been made over the past decades, the impact of these changes on the incidence and outcome of patients with diffuse alveolar hemorrhage has not been examined. We analyzed 1228 patients who underwent allogeneic hematopoietic stem cell transplantation between 2008-2015 at the University of Minnesota to study the incidence, risk factors, and outcomes of diffuse alveolar hemorrhage. Diffuse alveolar hemorrhage developed in 5% of allogeneic hematopoietic stem cell transplant recipients, at a median of 30 days (range +3 to +168 days) after transplantation. The incidence of diffuse alveolar hemorrhage was significantly greater in recipients of umbilical cord blood than peripheral blood or bone marrow grafts (HR: 2.08, 95% CI: 1.16-3.74; P=0.01). In multivariate analysis, delayed neutrophil engraftment or primary graft failure was a risk factor for diffuse alveolar hemorrhage following peripheral blood or bone marrow hematopoietic stem cell transplants (HR: 5.51, 95% CI: 1.26-24; P=0.02) and delayed platelet engraftment was associated with significantly increased diffuse alveolar hemorrhage in umbilical cord blood transplant recipients (HR: 6.96, 95% CI: 2.39-20.29; P<0.05). Myeloablative regimens including total body irradiation were also risk factors for diffuse alveolar hemorrhage (HR: 1.8, 95% CI: 1.03-3.13, P=0.05) in both peripheral blood or bone marrow and umbilical cord blood hematopoietic stem cell transplants (HR: 1.87, 95% CI: 0.95-3.71). Patients with diffuse alveolar hemorrhage had an inferior 6-month treatment-related mortality (HR: 6.09, 95% CI: 4.33-8.56, P<0.01) and 2-year overall survival (HR: 4.16, 95% CI: 3.06-5.64; P<0.01) using either graft source. The etiology of diffuse alveolar hemorrhage is multifactorial, involving lung injury influenced by high-dose total body irradiation, graft source, and delayed engraftment or graft failure. The survival of patients with diffuse alveolar hemorrhage after hematopoietic stem cell transplantation remains poor. Clinical interventions or experimental studies (e.g., cell expansion for umbilical cord blood transplants or thrombopoietin use) that modulate these risk factors may limit the incidence and improve the outcomes of diffuse alveolar hemorrhage.

Dataset Information

TANK prevents IFN-dependent fatal diffuse alveolar hemorrhage by suppressing DNA-cGAS aggregation.

Publications

TANK prevents IFN-dependent fatal diffuse alveolar hemorrhage by suppressing DNA-cGAS aggregation.

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