Abstract TMP24: Soluble St2 Links Innate Inflammation to Secondary Injury After Stroke and Subarachnoid Hemorrhage

Background: We recently found that soluble ST2 (sST2) is a plasma marker that predicts neurological outcome after ischemic stroke and aneurysmal subarachnoid hemorrhage. We sought to extend these findings by studying sST2 associations with markers of secondary brain injury and peripheral innate immunity. Methods: We studied 241 acute ischemic stroke (AIS) patients with sST2 level measured on admission (7.4 ± 3.7 hrs after stroke onset) and at least one follow-up brain imaging study, obtained at a mean of 2.2 ± 1.4 days after stroke onset. A subgroup (n=147) had a second sST2 measurement at a mean of 2.1 ± 1.7 days after stroke onset. A separate cohort of 110 subarachnoid hemorrhage (SAH) patients were studied who had plasma sST2 measured at approximately 3.5 ± 1.2 days after ictus. Markers of secondary brain injury included edema after AIS (midline shift), and delayed cerebral ischemia (DCI) or epileptiform discharges on EEG after SAH. The relationships between sST2 level and outcome measures were assessed. Primary blood mononuclear cells from SAH patients and elective aneurysm controls were analyzed by multiparameter flow cytometry to phenotype the peripheral immune response. Results: In the AIS cohort, baseline plasma sST2 level was associated with the presence of midline shift (46.1 vs. 41.8 ng/mL, p=0.017), which further increased at 48 hr after stroke onset (50.6 vs. 38.4 ng/mL, p=0.006). In the SAH cohort, median sST2 in patients who developed new epileptiform abnormalities was higher compared to patients who did not (114.8 ng/ml vs. 74.7 ng/ml, p=0.024). Higher median sST2 concentration was also observed in those patients with DCI (90.8 vs 53.7ng/mL, p=0.003). In patients with high sST2, flow cytometry identified a peripheral monocyte population with decreased expression of CD14 (4.27x105 ± 2950 A.U. vs. 5.64x105 ± 1290 A.U., p<0.001), and increased expression of CD16 (39,960 ± 272 A.U. vs. 34,869 ± 183 A.U., p<0.001). Conclusion: Plasma sST2 independently predicts edema after stroke, and DCI and epileptiform abnormalities after subarachnoid hemorrhage. Elevated sST2 is also associated with changes in peripheral innate immune cells. These data suggest that sST2 links the innate immune response to secondary brain injury.

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Innate immunity activation in the early brain injury period following subarachnoid hemorrhage

Journal of Neuroinflammation ◽

10.1186/s12974-019-1629-7 ◽

2019 ◽

Vol 16 (1) ◽

Cited By ~ 10

Author(s):

Typhaine Gris ◽

◽

Patrick Laplante ◽

Paméla Thebault ◽

Romain Cayrol ◽

...

Keyword(s):

Flow Cytometry ◽

Subarachnoid Hemorrhage ◽

Brain Injury ◽

Immune Cells ◽

Early Brain Injury ◽

Innate Immune ◽

Enzyme Linked Immunosorbent Assay ◽

Innate Immune Cells ◽

Time Points ◽

Systemic Inflammatory Disease

Abstract Background Aneurysmal subarachnoid hemorrhage (SAH) is a catastrophic disease with devastating consequences, including a high mortality rate and severe disabilities among survivors. Inflammation is induced following SAH, but the exact role and phenotype of innate immune cells remain poorly characterized. We investigated the inflammatory components of the early brain injury in an animal model and in SAH patients. Method SAH was induced through injection of blood in the subarachnoid space of C57Bl/6 J wild-type mice. Prospective blood collections were obtained at 12 h, days 1, 2, and 7 to evaluate the systemic inflammatory consequences of SAH by flow cytometry and enzyme-linked immunosorbent-assay (ELISA). Brains were collected, enzymatically digested, or fixed to characterize infiltrating inflammatory cells and neuronal death using flow cytometry and immunofluorescence. Phenotypic evaluation was performed at day 7 using the holding time and footprint tests. We then compared the identified inflammatory proteins to the profiles obtained from the plasma of 13 human SAH patients. Results Following SAH, systemic IL-6 levels increased rapidly, whereas IL-10 levels were reduced. Neutrophils were increased both in the brain and in the blood reflecting local and peripheral inflammation following SAH. More intracerebral pro-inflammatory monocytes were found at early time points. Astrocyte and microglia activation were also increased, and mice had severe motor deficits, which were associated with an increase in the percentage of caspase-3-positive apoptotic neurons. Similarly, we found that IL-6 levels in patients were rapidly increased following SAH. ICAM-1, bFGF, IL-7, IL-12p40, and MCP-4 variations over time were different between SAH patients with good versus bad outcomes. Moreover, high levels of Flt-1 and VEGF at admission were associated with worse outcomes. Conclusion SAH induces an early intracerebral infiltration and peripheral activation of innate immune cells. Furthermore, microglia and astrocytic activation are present at later time points. Our human and mouse data illustrate that SAH is a systemic inflammatory disease and that immune cells represent potential therapeutic targets to help this population of patients in need of new treatments.

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Evidence for a conditioning effect of inhalational anesthetics on angiographic vasospasm after aneurysmal subarachnoid hemorrhage

Journal of Neurosurgery ◽

10.3171/2019.3.jns183512 ◽

2020 ◽

Vol 133 (1) ◽

pp. 152-158 ◽

Cited By ~ 1

Author(s):

Umeshkumar Athiraman ◽

Diane Aum ◽

Ananth K. Vellimana ◽

Joshua W. Osbun ◽

Rajat Dhar ◽

...

Keyword(s):

Logistic Regression ◽

Subarachnoid Hemorrhage ◽

Brain Injury ◽

Aneurysmal Subarachnoid Hemorrhage ◽

Multivariate Logistic Regression Analysis ◽

Secondary Brain Injury ◽

Large Artery ◽

Inhalational Anesthetics ◽

Angiographic Vasospasm ◽

Inhalational Anesthetic

OBJECTIVEDelayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage (SAH) is characterized by large-artery vasospasm, distal autoregulatory dysfunction, cortical spreading depression, and microvessel thrombi. Large-artery vasospasm has been identified as an independent predictor of poor outcome in numerous studies. Recently, several animal studies have identified a strong protective role for inhalational anesthetics against secondary brain injury after SAH including DCI—a phenomenon referred to as anesthetic conditioning. The aim of the present study was to assess the potential role of inhalational anesthetics against cerebral vasospasm and DCI in patients suffering from an SAH.METHODSAfter IRB approval, data were collected retrospectively for all SAH patients admitted to the authors’ hospital between January 1, 2010, and December 31, 2013, who received general anesthesia with either inhalational anesthetics only (sevoflurane or desflurane) or combined inhalational (sevoflurane or desflurane) and intravenous (propofol) anesthetics during aneurysm treatment. The primary outcomes were development of angiographic vasospasm and development of DCI during hospitalization. Univariate and logistic regression analyses were performed to identify independent predictors of these endpoints.RESULTSThe cohort included 157 SAH patients whose mean age was 56 ± 14 (± SD). An inhalational anesthetic–only technique was employed in 119 patients (76%), while a combination of inhalational and intravenous anesthetics was employed in 34 patients (22%). As expected, patients in the inhalational anesthetic–only group were exposed to significantly more inhalational agent than patients in the combination anesthetic group (p < 0.05). Multivariate logistic regression analysis identified inhalational anesthetic–only technique (OR 0.35, 95% CI 0.14–0.89), Hunt and Hess grade (OR 1.51, 95% CI 1.03–2.22), and diabetes (OR 0.19, 95% CI 0.06–0.55) as significant predictors of angiographic vasospasm. In contradistinction, the inhalational anesthetic–only technique had no significant impact on the incidence of DCI or functional outcome at discharge, though greater exposure to desflurane (as measured by end-tidal concentration) was associated with a lower incidence of DCI.CONCLUSIONSThese data represent the first evidence in humans that inhalational anesthetics may exert a conditioning protective effect against angiographic vasospasm in SAH patients. Future studies will be needed to determine whether optimized inhalational anesthetic paradigms produce definitive protection against angiographic vasospasm; whether they protect against other events leading to secondary brain injury after SAH, including microvascular thrombi, autoregulatory dysfunction, blood-brain barrier breakdown, neuroinflammation, and neuronal cell death; and, if so, whether this protection ultimately improves patient outcome.

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Stereotactic cisternal lavage in patients with aneurysmal subarachnoid hemorrhage with urokinase and nimodipine for the prevention of secondary brain injury (SPLASH): study protocol for a randomized controlled trial

Trials ◽

10.1186/s13063-021-05208-6 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Roland Roelz ◽

Fabian Schubach ◽

Volker A. Coenen ◽

Carolin Jenkner ◽

Christian Scheiwe ◽

...

Keyword(s):

Clinical Trials ◽

Subarachnoid Hemorrhage ◽

Brain Injury ◽

Neurological Outcome ◽

Aneurysmal Subarachnoid Hemorrhage ◽

Standard Of Care ◽

Secondary Brain Injury ◽

Ringer’S Solution ◽

Randomized Controlled ◽

Therapy Protocol

Abstract Background Delayed cerebral infarction (DCI) is a major cause of death and poor neurological outcome in patients with aneurysmal subarachnoid hemorrhage (aSAH). Direct intrathecal therapies with fibrinolytic and spasmolytic drugs have appeared promising in clinical trials. However, access to the subarachnoid space for intrathecal drug administration is an unsolved problem so far, especially in patients with endovascular aneurysm securing. We investigate a therapy protocol based on stereotactic catheter ventriculocisternostomy (STX-VCS), a new approach to overcome this problem. The primary objective of this study is to assess whether cisternal lavage with urokinase, nimodipine, and Ringer’s solution administered via a stereotactically implanted catheter into the basal cisterns (= investigational treatment (IT)) is safe and improves neurological outcome in patients with aSAH. Methods This is a randomized, controlled, parallel-group, open-label phase II trial. Fifty-four patients with severe aSAH (WFNS grade ≥ 3) will be enrolled at one academic tertiary care center in Southern Germany. Patients will be randomized at a ratio of 1:1 to receive either standard of care only or standard of care plus the IT. The primary endpoint is the proportion of subjects with a favorable outcome on the Modified Rankin Scale (defined as mRS 0–3) at 6 months after aSAH. Further clinical and surrogate outcome parameters are defined as secondary endpoints. Discussion New approaches for the prevention and therapy of secondary brain injury in patients with aSAH are urgently needed. We propose this RCT to assess the clinical safety and efficacy of a novel therapy protocol for intrathecal administration of urokinase, nimodipine, and Ringer’s solution. Trial registration Deutsches Register Klinischer Studien (German Clinical Trials Register), DRKS00015645. Registered on 8 May 2019

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Cerebrospinal fluid hemoglobin drives subarachnoid hemorrhage-related secondary brain injury

Brain and Spine ◽

10.1016/j.bas.2021.100310 ◽

2021 ◽

Vol 1 ◽

pp. 100310

Author(s):

K. Akeret ◽

R.M. Buzzi ◽

C.A. Schaer ◽

B.R. Thomson ◽

F. Vallelian ◽

...

Keyword(s):

Cerebrospinal Fluid ◽

Subarachnoid Hemorrhage ◽

Brain Injury ◽

Secondary Brain Injury

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Effect of heparin on secondary brain injury in patients with subarachnoid hemorrhage: an additional ‘H’ therapy in vasospasm treatment

Journal of NeuroInterventional Surgery ◽

10.1136/neurintsurg-2016-012925 ◽

2017 ◽

Vol 9 (7) ◽

pp. 659-663 ◽

Cited By ~ 8

Author(s):

Markus Bruder ◽

Sae-Yeon Won ◽

Sepide Kashefiolasl ◽

Marlies Wagner ◽

Nina Brawanski ◽

...

Keyword(s):

Subarachnoid Hemorrhage ◽

Brain Injury ◽

Aneurysmal Subarachnoid Hemorrhage ◽

Favorable Outcome ◽

Matched Pair ◽

Control Group ◽

High Morbidity ◽

Secondary Brain Injury ◽

Heparin Group ◽

Vasomotor Function

ObjectiveSecondary brain injury leads to high morbidity and mortality rates in patients with aneurysmal subarachnoid hemorrhage (aSAH). However, evidence-based treatment strategies are sparse. Since heparin has various effects on neuroinflammation, microthromboembolism and vasomotor function, our objective was to determine whether heparin can be used as a multitarget prophylactic agent to ameliorate morbidity in SAH.MethodsBetween June 1999 and December 2014, 718 patients received endovascular treatment after rupture of an intracranial aneurysm at our institution; 197 of them were treated with continuous unfractionated heparin in therapeutic dosages after the endovascular procedure. We performed a matched pair analysis to evaluate the effect of heparin on cerebral vasospasm (CVS), cerebral infarction (CI), and outcome.ResultsThe rate of severe CVS was significantly reduced in the heparin group compared with the control group (14.2% vs 25.4%; p=0.005). CI and multiple ischemic lesions were less often present in patients with heparin treatment. These effects were enhanced if patients were treated with heparin for >48 hours, but the difference was not significant. Favorable outcome at 6-month follow-up was achieved in 69% in the heparin group and in 65% in the control group.ConclusionsPatients receiving unfractionated continuous heparin after endovascular aneurysm occlusion have a significant reduction in the rate of severe CVS, have CI less often, and tend to have a favorable outcome more often. Our findings support the potential beneficial effects of heparin as a multitarget therapy in patients with SAH, resulting in an additional ‘H’ therapy in vasospasm treatment.

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Guilty Molecules, Guilty Minds? The Conflicting Roles of the Innate Immune Response to Traumatic Brain Injury

Mediators of Inflammation ◽

10.1155/2012/356494 ◽

2012 ◽

Vol 2012 ◽

pp. 1-18 ◽

Cited By ~ 17

Author(s):

Sarah Claire Hellewell ◽

Maria Cristina Morganti-Kossmann

Keyword(s):

Traumatic Brain Injury ◽

Immune Response ◽

Brain Injury ◽

Innate Immune Response ◽

Complex Disease ◽

Clinical Care ◽

The Body ◽

Innate Immune ◽

Neuroprotective Therapy ◽

Attractive Therapeutic Target

Traumatic brain injury (TBI) is a complex disease in the most complex organ of the body, whose victims endure lifelong debilitating physical, emotional, and psychosocial consequences. Despite advances in clinical care, there is no effective neuroprotective therapy for TBI, with almost every compound showing promise experimentally having disappointing results in the clinic. The complex and highly interrelated innate immune responses govern both the beneficial and deleterious molecular consequences of TBI and are present as an attractive therapeutic target. This paper discusses the positive, negative, and often conflicting roles of the innate immune response to TBI in both an experimental and clinical settings and highlights recent advances in the search for therapeutic candidates for the treatment of TBI.

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The Effects of Brain Injury on Heart Rate Variability and the Innate Immune Response in Critically Ill Patients

Journal of Neurotrauma ◽

10.1089/neu.2011.2035 ◽

2012 ◽

Vol 29 (5) ◽

pp. 747-755 ◽

Cited By ~ 32

Author(s):

Matthijs Kox ◽

Maarten Q. Vrouwenvelder ◽

Jan C. Pompe ◽

Johannes G. van der Hoeven ◽

Peter Pickkers ◽

...

Keyword(s):

Heart Rate ◽

Immune Response ◽

Heart Rate Variability ◽

Brain Injury ◽

Critically Ill ◽

Innate Immune Response ◽

Critically Ill Patients ◽

Innate Immune

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Iron Overload Diminishes the Effectiveness of the Innate Immune Response in Thalassemia Major: a Possible Mechanism for Increased Infection Risk.

Blood ◽

10.1182/blood.v114.22.4071.4071 ◽

2009 ◽

Vol 114 (22) ◽

pp. 4071-4071

Author(s):

Patrick B Walter ◽

Paul R Harmatz ◽

Annie Higa ◽

David Killilea ◽

Nancy Sweeters ◽

...

Keyword(s):

Flow Cytometry ◽

Immune Response ◽

Iron Overload ◽

Board Of Directors ◽

Innate Immune Response ◽

Research Funding ◽

Innate Immune ◽

Healthy Controls ◽

Advisory Committees ◽

Fluorescent Intensity

Abstract Abstract 4071 Poster Board III-1006 Introduction Infection is the second most common cause of death in thalassemia. The innate immune system provides a first line of defense against infection and specificity depends on pattern recognition receptors (PRRs) specific to microbial pathogens. One class of PRR called the toll-like receptors (TLRs) are important for transducing the signal for bacterial Lipopolysaccharide (LPS), resulting not only in cytokine production, but also in the control of extracellular iron levels through production of neutrophil gelatinase associated Lipocalin (NGAL). However, the exact role that NGAL plays and the expression level of PRRs are unknown in thalassemia. Thus, the goal in these studies is to investigate the relationship of iron overload to the innate immune cell expression of PRRs and NGAL in thalassemia. Patients and Methods Fifteen transfusion dependent thalassemia patients (11 – 29 yrs old) participating in the combination trial of deferasirox (an oral iron chelator) and deferoxamine were enrolled (Novartis sponsored CICL670AUS24T). Fasting blood samples were obtained i) at baseline after a 72 hr washout of chelator, and ii) at 6 and 12 months on study. Five healthy controls (13 - 18 yrs old) were also enrolled. Fresh monocytes were isolated using antibody-linked magnetic microbeads (Miltenyi Biotec Inc). Highly enriched populations of CD14+ monocytes were verified by flow cytometry. The expression of TLR4, also examined by flow cytometry is reported as the mean fluorescent intensity (MFI). In patients with thalassemia, liver iron concentration (LIC) was analyzed by biomagnetic susceptibility (“SQUID”, Ferritometer®). The plasma levels of NGAL were analyzed by ELISA. Results At baseline the expression of monocyte TLR4 (mean 18.8 ± 3.5 MFI) was reduced 30% compared to the healthy controls (mean 26.9 ± 7.6 MFI, p<0.05). The expression of TLR4 over the follow-up period of 52 weeks in patients receiving intensive combination chelator therapy significantly increased 27% / year (7 MFI / year, p=0.005). Interestingly the expression of monocyte TLR4 was negatively correlated with LIC (r=-0.6, p=0.04). Finally, thalassemia patients at baseline have significantly higher levels of NGAL (80 ± 20 ng/ml) compared to controls (42 ± 15 ng/ml, p=0.01). Conclusions These preliminary studies support the hypothesis that iron burden has a negative impact on the innate immune response in thalassemia as demonstrated by the decreased expression of TLR4. After intensive chelation, the levels of TLR4 increased, indicating that decreased iron overload with chelation may improve innate immune responsiveness. Finally, the iron transport protein NGAL is significantly elevated in thalassemia possibly acting to prevent essential iron uptake by pathogenic bacteria. Disclosures: Harmatz: Novartis: Research Funding; Apotex : Membership on an entity's Board of Directors or advisory committees; Ferrokin: Membership on an entity's Board of Directors or advisory committees. Vichinsky:Novartis: Consultancy, Research Funding.

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Microglial Metabolism After Pediatric Traumatic Brain Injury – Overlooked Bystanders or Active Participants?

Frontiers in Neurology ◽

10.3389/fneur.2020.626999 ◽

2021 ◽

Vol 11 ◽

Author(s):

Aria C. Shi ◽

Ursula Rohlwink ◽

Susanna Scafidi ◽

Sujatha Kannan

Keyword(s):

Traumatic Brain Injury ◽

Immune Response ◽

Brain Injury ◽

Innate Immune Response ◽

Innate Immune ◽

Metabolic Alterations ◽

Microglial Phenotype ◽

Integral Role ◽

And Behavior ◽

The Brain

Microglia play an integral role in brain development but are also crucial for repair and recovery after traumatic brain injury (TBI). TBI induces an intense innate immune response in the immature, developing brain that is associated with acute and chronic changes in microglial function. These changes contribute to long-lasting consequences on development, neurologic function, and behavior. Although alterations in glucose metabolism are well-described after TBI, the bulk of the data is focused on metabolic alterations in astrocytes and neurons. To date, the interplay between alterations in intracellular metabolic pathways in microglia and the innate immune response in the brain following an injury is not well-studied. In this review, we broadly discuss the microglial responses after TBI. In addition, we highlight reported metabolic alterations in microglia and macrophages, and provide perspective on how changes in glucose, fatty acid, and amino acid metabolism can influence and modulate the microglial phenotype and response to injury.

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The Impact of NFAT Inhibition on Neutrophil Antifungal Defense and Myelopoiesis in Cyclosporine A Treated and NFATc1LysM Mice

Blood ◽

10.1182/blood.v126.23.1007.1007 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1007-1007

Author(s):

Daniel Teschner ◽

Christian Michel ◽

Steve Pruefer ◽

Matthias Theobald ◽

Hansjoerg Schild ◽

...

Keyword(s):

Bone Marrow ◽

Flow Cytometry ◽

Immune Response ◽

Progenitor Cells ◽

Pulmonary Inflammation ◽

Innate Immune ◽

Myeloid Differentiation ◽

Myeloid Progenitor ◽

Myeloid Progenitor Cells

Abstract Background and Aims: Immunodeficient patients after allogeneic stem cell transplantation (HSCT) are heavily threatened by opportunistic fungal infections like invasive pulmonary aspergillosis (IPA), partly due to immunosuppressive medication e.g. by calcineurin inhibitors like cyclosporine A (CsA) or tacrolimus. It is well known that the nuclear factor of activated T cells (NFAT) is an important transcription factor downstream of calcineurin in the adaptive immune system especially in T cells. Additionally, there is a growing body of evidence that NFAT also plays a substantial role in innate immune response against invasive fungal diseases by polymorphonuclear neutrophils (PMN), as well as in regulation of myelopoiesis and myeloid differentiation, as indicated by recent data in rodent models. Methods: Firstly, we used a murine IPA model (C57BL/6) to clarify the role of NFAT in antifungal innate immune response in vivo. To do so, we treated mice intraperitoneally with CsA (18mg/kg/d) or vehicle for 2 weeks and challenged them with Aspergillus fumigatus (A. f.) conidia intratracheally. 24 hours later, some mice were sacrificed and PMN recruitment to the lungs and pulmonary fungal clearance were examined by analyzing bronchoalveolar lavages (BAL) and peripheral blood (PB) by flow cytometry and murine lungs by fungal culture assays and histopathologic examination. In addition, survival of remaining infected mice was studied with neutropenic animals (by depletion with anti-Gr1) serving as positive controls. Secondly, LysM-specific NFATc1 knockout (NFATc1LysM) mice were bred lacking NFATc1 expression solely in myelomonocytic cells (i.e. PMN and monocytes). Furthermore, these animals were infected with A. f. and analyzed as described above. Secondly, we investigated myelopoiesis and myeloid differentiation under steady state conditions by quantifying bone marrow derived myeloid progenitor cells from CsA treated or NFATc1LysM mice using flow cytometry and simultaneously counting PMN in PB. Results: While the infection was lethal in CsA or vehicle treated neutropenic mice, all CsA or vehicle treated mice survived the infection. CsA treated mice showed enhanced PMN recruitment in BAL by trend (55.2% +/- 12.0 (CsA) vs. 33.7% +/- 8.0 (control), mean +/- SEM, p=0.053), whereas pulmonary inflammation and PMN counts in PB were comparable to controls. In contrast, fungal clearance was clearly impaired in animals after CsA treatment (2.1 x 105 CFU/lung after 48 hours +/- 0.5 (CsA) vs. 1.7 x 105 +/- 0.2 (control), p<0.005). Along with that, NFATc1LysM mice infected with A. f. showed unimpaired survival. However, there were no detectable differences in PMN recruitment or fungal clearance, whereas pulmonary inflammation and PMN counts in PB seemed to be more pronounced in knockout mice (1.0 inflammation points/lung +/- 0.12 (NFATc1LysM) vs. 0.7 +/- 0.07 (control), p=0.057; 1.5 x 103 PMN/µl +/- 0.2 (NFATc1LysM) vs. 0.9 +/- 0.1 (control), p=0.036). Distribution of bone marrow derived murine myeloid progenitor cells was unaffected through NFAT inhibition by CsA but clearly impaired in NFATc1LysM mice especially in megakaryocyte-erythroid progenitor cells (1.2 x 105 cells +/- 0.2 (NFATc1LysM) vs. 2.7 +/- 0.6, p=0.015) whereas PMN blood counts in PB were unchanged. Conclusions: In a mouse model, NFAT inhibition via treatment with CsA does not influence survival after infection with A. f. in vivo but affects PMN recruitment and local fungal clearance. To some extent this may be due to impaired PMN phagocytic and migratory capabilities as indicated by our in vitro and ex vivo studies (data not shown). However, solely NFATc1 downregulation in PMN apparently results in slightly different effects given that infected NFATc1LysM mice displayed enhanced pulmonary inflammation and elevated PMN blood counts compared to controls. Additionally, NFATc1 inhibition in NFATc1LysM mice leads to constrained myelopoiesis under steady state conditions without affecting peripheral PMN blood counts compared to untreated wild type controls. Further studies are needed to clarify underlying mechanisms and clinical relevance in HSCT of our findings. Disclosures No relevant conflicts of interest to declare.

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