scholarly journals A novel IL-10 – DEL-1 axis promotes granulopoiesis and sepsis survival in early life

2021 ◽  
Author(s):  
Eleni Vergadi ◽  
Ourania Kolliniati ◽  
Konstantina Lyroni ◽  
Eleftheria Ieronymaki ◽  
Ioanna Lapi ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Neonatal Sepsis ◽  
Early Life ◽  
Host Response ◽  
Mortality Rates ◽  
Susceptibility To Infection ◽  
Adult Mice ◽  
Sepsis Survival ◽  
Neutrophil Kinetics

Abstract Newborns’ susceptibility to infection is mainly attributed to decreased neutrophil bone marrow reserves and peripheral blood neutropenia. However, the regulation of neonatal neutrophil kinetics in sepsis remains poorly understood. We demonstrate herein that the developmental endothelial locus (DEL-1) is elevated in early life and is integral to a protective host response in neonates, by supporting emergency granulopoiesis. DEL-1-deficient neonate mouse pups subjected to sepsis displayed diminished bone marrow numbers of neutrophils and granulocyte-macrophage progenitors, leading to neutropenia, exaggerated bacteremia, and increased mortality; defects that were rescued by DEL-1 administration. Contrary to adult mice, DEL-1 was not downregulated upon neonatal sepsis. The sustained production of DEL-1 under newborn sepsis was attributed to a high IL-10/IL-17A ratio, as we IL-10 upregulated DEL-1. The expression of DEL-1 and its effect in emergency granulopoiesis in neonates was diminished by anti-IL-10-Receptor blockage. Consistent with the mouse findings, DEL-1 and neutrophil numbers were higher in septic human adult and neonate patients with high IL-10/IL-17A ratio. Furthermore, septic patients with high DEL-1 exhibited lower mortality rates compared to patients with low DEL-1. These findings highlight the role of a hitherto unappreciated IL-10–DEL-1 axis in supporting emergency granulopoiesis, preventing neutropenia and promoting sepsis survival in early life.

scholarly journals Critical Role of Prostaglandin E2Overproduction in Impaired Pulmonary Host Response following Bone Marrow Transplantation

2006 ◽  
Vol 177 (8) ◽  
pp. 5499-5508 ◽  
Author(s):  
Megan N. Ballinger ◽  
David M. Aronoff ◽  
Tracy R. McMillan ◽  
Kenneth R. Cooke ◽  
Krystyna Olkiewicz ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Marrow Transplantation ◽  
Host Response ◽  
Critical Role

scholarly journals Dicer Ablations in Bone Marrow Niche Impair Hematopoietic Progenitor/Stem Cells and Induce Myelodysplasia in Young Mice but Are Dispensable for Adult Hematopoiesis

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1196-1196 ◽  
Author(s):  
Bijender Kumar ◽  
Mayra Garcia ◽  
Guido Marcucci ◽  
Ching-Cheng Chen
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Embryonic Development ◽  
Bone Marrow Niche ◽  
Hematopoietic Progenitors ◽  
Mirna Processing ◽  
Adult Mice ◽  
Hsc Niche ◽  
Young Mice

Abstract MicroRNAs (miRNAs) regulate hematopoietic cell fate and their global down-regulation by Dicer1 deletion promotes tumorigenesis in a cancer-cell-autonomous manner (Kumar M.S. et al, 2007). Raajimakers MH et al. (2010) using neonatal Osterix specific dicer deletion showed altered hematopoiesis and developed myelodysplasia. However, there is no study illustrating the role of the ablation of bone marrow (BM) niche specific miRNA processing machinery in the adult mice. Since expression and functions of different mesenchymal and osteoprogenitors vary from embryonic development to adulthood, studying the dicer ablation in adult mice may provide more insight about the role of miRNA processing in adult mice niche. Here we investigate whether adult Osterix expressing cells play a similar role in the HSC niche compared to fetal Osterix expressing cells. We crossed Osx-GFP-tTA-Cre recombinase mice with mice with floxed Dicer1 allele. Crossing generated Osx- GFP-tTA-Cre+Dicerfl/+ (OCDfl/+control) and Osx-GFP- tTA-Cre+ Dicerfl/fl (OCDfl/fl mutant) mice. Osx-GFP-tTA-Cre expression was either activated during embryonic development (young dicer KO) or suppressed using tetracycline until mice were 6 weeks of age (adult dicer KO). We found young dicer KO mice had reduced weight (p=0.0031), leukopenia, anemia, reduced mature CD19+B220- B lymphocytes (p=0.0034) and increased CD11b+Gr- monocytes and CD11b+Gr+ neutrophils (p=0.02 and p=0.04 respectively) in peripheral blood compared to OCDfl/+ control aged littler mates. The leucocytes and platelets showed dysplastic changes suggestive of myelodysplasia and had extra-medullary hematopoiesis. Adult dice KO, on the other hand, show no leukemia development 6 months after Cre activation. The number of BM hematopoietic progenitors (Lin-Sca1+ c-Kit+ cells, LSK) and long term hematopoietic stem cells (LT-HSCs, LSK CD150+CD48+ cells) in young dicer KO mice were significantly reduced compared to age matched control (OCDfl/+ control) mice. We observed increased Annexin V positive LSK, LT-HSCs and megakaryocytes erythroid progenitors (MEP) in the young dicer KO mice indicating increased apoptosis. Adult dicer KO mice didn't have significant changes in apoptosis in different hematopoietic progenitors. In young dicer KO mice, BM derived LSK and LT-HSCs showed increased cycling (SG2M phase, p=0.0133) and less quiescenece (Go phase, p=0.013). However LT-HSC from adult dicer KO didn't show any difference in cell cycling (p=0.18 and 0.09 respectively). Together these results indicate that while Osterix expressing cells in fetal and young mice give rise to a variety of HSC niche supporting cells the adult expression is limited to more mature osteoblast that are not absolutely essential for HSC maintenance. Our study provides the rationale for further exploration of the complexity in hierarchy of activity within niche constituting mesenchymal stroma progenitors and their role in different developmental stages to maintain hematopoiesis. Disclosures No relevant conflicts of interest to declare.

Vav1, a Rho GTPase Guanine Exchange Factor (GEF) Is Required to Integrate gp130 Cytokine Signaling for Successful Engraftment of Murine Hematopoietic Stem Cells Following Irradiation

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2149-2149
Author(s):  
Serena De Vita ◽  
Yanhua Li ◽  
Chad Everett Harris ◽  
Meaghan McGuinness ◽  
David A. Williams
Keyword(s):  
Bone Marrow ◽  
Stromal Cells ◽  
Rho Gtpase ◽  
Macrocytic Anemia ◽  
Cytokine Signaling ◽  
Newborn Mice ◽  
Hematopoietic Stem ◽  
Adult Mice

Abstract Successful engraftment of hematopoietic stem and progenitor cells (HSPCs) during bone marrow transplantation requires appropriate homing and retention of transplanted cells in the bone marrow (BM) and the activation of a proliferative program in response to signals from the hematopoietic microenvironment (HM). Molecular pathways regulating migration, homing and retention of HSPCs in the BM are integrated by RhoGTPasesincluding Rac and CDC42, however the complex cues that drive the proliferative response of these cells following transplantation are less clear. We have previously described the hematopoietic phenotype of adult mice lacking Vav1, a multi-domain, hematopoietic-specific GEF for Rac and CDC42. Deletion of Vav1 does not affect steady state hematopoiesis in adult mice, but severely compromises the engraftment potential of HSPCs. In the absence of Vav1, signal transduction from SDF1α is impaired in HSPCs, leading to abnormal localization and reduced retention of these cells in the HM, a phenotype similar to deficiency of Rac (Sanchez-Aguilera et al. PNAS, 2011). Here, we define an unexpected role for Vav1 in mediating post-irradiation proliferative responses of HSPCs. Surprisingly, we observed that deletion of Vav1 does not affect HSPC migration during ontogeny, a process largely mediated by SDF1α. The number of immunophenotypically and functionally defined HSPCs in Vav1-/- E13.5 fetal liver (FL) was comparable to WT (Table 1). Similarly, no difference was detected in HSPCs in the peripheral blood (PB) of E18.5 embryos or in the BM of newborn mice. However, similar to adult cells, Vav1-/- fetal HSCPs showed severely defective engraftment in lethally irradiated recipients (see Table 2). In marked contrast, both adult and fetal Vav1-/- HSCPs could engraft non-irradiated (Kit W/Wv Rag2- γc-) recipients, achieving successful correction of the macrocytic anemia and B cell leukopenia phenotype of recipient mice (Table 2, in red). Reduced proliferation of Vav1-/- HSPCs was also observed in vitro upon co-culture with primary irradiated stromal cells (Table 3). No differences among genotypes were detected when using non-irradiated stromal cells. These data suggest a distinct role for Vav1 in mediating responses of HSPCs to the HM after irradiation. To further clarify this phenotype, we investigated the role of individual soluble factors on proliferative responses of Vav1 HSPCs. Given their known role in expansion and proliferation of hematopoietic progenitors we focused on gp130 cytokines. We found that both IL-6 and IL-11, prominent members of this cytokine family, were increased in the BM of irradiated WT recipients, compared to both non-irradiated WT recipients (3x and 2x increase) and Kit W/Wv Rag2- γc- (2x and 3x increase) age- and sex-matched animals. To validate the potential role of IL-6 and IL-11 in Vav1 function, we stimulated HSPCs with both cytokines and observed that they induced phosphorylation of Vav1 and activation of Rac, but not CDC42. Using CFU assays, liquid culture experiments and BrdU analysis we confirmed that deletion of Vav1 abolishes the proliferative responses elicited by IL-6 and IL-11 on HSPCs in vitro. In summary, we show that Vav1 acts in HSPCs to mitigate responses to pro-inflammatory cytokines present in the HM during engraftment following irradiation. Manipulating the gp130-Vav-Rac axis in HSPCs could represent a strategy to enhance engraftment of normal cells in conditioned recipients. Disclosures Williams: bluebird bio: Research Funding; Novartis: Consultancy; Orchard Therapeutics: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Lung expression of genes encoding SARS-CoV-2 cell entry molecules and antiviral restriction factors: interindividual differences are associated with age and germline variants

2020 ◽  
Author(s):  
Chiara E. Cotroneo ◽  
Nunzia Mangano ◽  
Tommaso A. Dragani ◽  
Francesca Colombo
Keyword(s):  
Virus Replication ◽  
Lung Tissue ◽  
Quantitative Trait ◽  
Host Response ◽  
Cell Entry ◽  
Interindividual Differences ◽  
Susceptibility To Infection ◽  
Antiviral Responses ◽  
Diseased Lung

AbstractGermline variants in genes involved in SARS-CoV-2 cell entry (i.e. ACE2 and TMPRSS2) may influence the susceptibility to infection, as may polymorphisms in genes involved in the innate host response to viruses (e.g. APOBEC3 family). We searched for polymorphisms acting, in lung tissue, as expression quantitative trait loci (eQTLs) for 15 candidate COVID-19 susceptibility genes, selected for their roles in virus cell entry and host antiviral responses. No significant eQTLs were identified for ACE2 and TMPRSS2 genes, whose expression levels did not associate with either sex or age of the 408 patients whose non-diseased lung tissue was analyzed. Instead, we identified seven cis-eQTLs (FDR<0.05) for APOBEC3D and APOBEC3G (rs139296, rs9611092, rs139331, rs8177832, rs17537581, rs61362448, and rs738469). The genetic control of the expression of APOBEC3 genes, which encode enzymes that interfere with virus replication, may explain interindividual differences in risk or severity of viral infections. Future studies should investigate the role of host genetics in COVID-19 patients using a genome-wide approach, to identify other genes whose expression levels are associated with susceptibility to SARS-CoV-2 infection or COVID-19 severity.Author summaryIdentification of expression quantitative trait loci (eQTLs) has become commonplace in functional studies on the role of individual genetic variants in susceptibility to diseases. In COVID-19, it has been proposed that individual variants in SARS-CoV-2 cell entry and innate host response genes may influence the susceptibility to infection. We searched for polymorphisms acting, in non-diseased lung tissue of 408 patients, as eQTLs for 15 candidate COVID-19 susceptibility genes, selected for their roles in virus cell entry and host antiviral responses. Seven cis-eQTLs were detected for APOBEC3D and APOBEC3G genes, which encode enzymes that interfere with virus replication. No significant eQTLs were identified for ACE2 and TMPRSS2 genes. Therefore, the identified eQTLs may represent candidate loci modulating interindividual differences in risk or severity of SARS-CoV-2 virus infection.

scholarly journals Hepatic Leukemia Factor Is Critical for Hematopoietic Stem Cells and Promotes MLL-AF9 Acute Myeloid Leukemia

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2466-2466
Author(s):  
Aurelie Baudet ◽  
Karolina Paulina Komorowska ◽  
Hultmark Simon ◽  
Marcus Järås ◽  
Marion Chapellier ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Fusion Protein ◽  
Fetal Liver ◽  
Leukemia Cells ◽  
Hematopoietic Stem ◽  
Aged Mice ◽  
Adult Mice ◽  
Leukemia Development

The transcription factor Hepatic leukemia factor (HLF), initially identified as part of a leukemic fusion protein (E2A-HLF) causing B-lymphoid leukemia in children, is expressed in a wide range of tissues. In the mouse hematopoietic system, HLF is highly expressed in hematopoietic stem cells while being hardly detectable in more restricted progenitor populations. We have previously shown that in adult mice, HLF is essential for preserving the hematopoietic stem cell (HSC) pool during regeneration by maintaining their quiescence (Komorowska et al, Cell reports, 2017). Notably, despite this highly specific expression profile and a critical role in hematopoietic regeneration, mice with double knock-out of HLF alleles (KO) appeared to age normally (18-24 months survival > 90% for both WT and KO). In this study, we investigated the role of HLF in HSC during aging and leukemogenesis. We first confirmed that HLF is expressed all through ontogeny by performing quantitative PCR on HSC and progenitor populations from mouse fetal liver (E14.5 FL) and bone marrow (BM) of aged mice (18-month-old mice). We found that not only is HLF expressed in hematopoietic cells from embryonic to aged mice, but also that the expression profile was highly conserved. In fact, we found that HLF expression decreased during hematopoietic differentiation independently of ontogenic age (HLF/HPRT relative expression: 6 in HSC (LSK-CD150+CD48-), 3 in HSPC (LSK), and <0,2 in CMP (Lin-kit+sca1-CD34+CD16/32-), GMP (Lin-kit+sca1-CD34+CD16/32+), and MEP (Lin-kit+sca1-CD34-CD16/32-). Additionally, hematopoietic parameters as well as lineage distribution in peripheral blood and bone marrow of aged KO mice were within normal range (at the exception of a 50% reduction in platelet blood count, also reported in adult mice). While we found no significant difference in the frequency of immunophenotypic HSC in total BM (LSK-CD34-Flt3-; WT: 0,0006 %, KO: 0,0004 %), aged KO grafts (200 000 total BM cells in 1:1 ratio with competitor) demonstrated a defective capacity to reconstitute primary recipients (donor contribution, WT: 60%, KO: 45 %). In secondary recipients, the defect was further aggravated (donor contribution; WT: 60 %, KO: 20%). Because neither SLAM nor CD34 markers can be used in KO FL, we quantified the percentage of EPCR+ cells within the LSK compartment as a surrogate marker for HSC and found a 2-fold decrease compared to WT controls. In competitive transplantations, KO E14.5 fetal liver cells demonstrated an impaired regenerative capacity in primary (donor contribution; WT: 88.8% (SEM 6.2), KO 63% SEM (16.2); n>5) and secondary recipients (donor contribution: WT: 67% (SEM 2.7), KO: 8.4% (SEM 3.6), n=4). In addition to its function in healthy hematopoiesis, studies have suggested that HLF is a downstream mediator of the MLL/AF9 (MA9) leukemic fusion protein. To address the contribution of HLF to MA9 leukemogenesis, mice were transplanted with either KO- or WT-BM-derived c-Kit+ cells expressing the MA9 fusion protein. Preliminary results showed that HLF did not affect the latency of the leukemia in primary recipients with mice succumbing to a lethal disease at days 40-41 after transplant independently of the leukemic graft genetic background. However, KO leukemic cells had a significantly delayed leukemia development in secondary recipients (time to death; WT: 32-39 days, KO: 39-68 days). Moreover, semi-quantitative PCR showed that not only was HLF expressed in leukemia cells harvested from primary recipients but also that the expression level displayed a tendency to an increase in leukemia cells from secondary recipients. Altogether, our data suggest that while HLF may be dispensable for leukemic transformation, it promotes the development of MLL-AF9 leukemia in mice. We are currently in the process of confirming the role of HLF in MA9 leukemia development. Taken together, we here show that HLF is essential for HSCs from embryonic to aged mice. We further show that HLF is critical for serial propagation of AML cells, suggesting that HLF is needed to maintain leukemia stem cells. Disclosures No relevant conflicts of interest to declare.

scholarly journals Elevated levels of interleukin-27 in early life compromise protective immunity during neonatal sepsis

2019 ◽  
Author(s):  
Brittany G. Seman ◽  
Jordan K. Vance ◽  
Travis W. Rawson ◽  
Michelle R. Witt ◽  
Annalisa B. Huckaby ◽  
...  
Keyword(s):  
Immune Response ◽  
Bacterial Infection ◽  
Neonatal Sepsis ◽  
Early Life ◽  
Host Response ◽  
Protective Immune Response ◽  
Bacterial Killing ◽  
Increased Risk ◽  
The Impact ◽  
Neonatal Population

ABSTRACTNeonates are at increased risk for bacterial sepsis as a result of immature immunity. We established that the immune suppressive cytokine interleukin (IL)-27 is elevated in early life. In the present work, we hypothesized that increased levels of IL-27 may predispose the neonatal population to more severe infection during sepsis. In a neonatal sepsis model, systemic IL-27 levels continued to rise during infection. Peripheral tissue analysis revealed systemic IL-27 expression, while myeloid cell profiling identified Gr-1 and F4/80-expressing cells as the most abundant producers of IL-27 during infection. Increased IL-27 levels were consistent with increased mortality that was improved in WSX-1-/- mice that lack a functional IL-27 receptor. Infected WSX-1-/- pups exhibited improved weight gain and reduced morbidity. IL-27 signaling in WT mice promoted increased bacterial burdens and systemic inflammation compared to WSX-1-/- neonates. This was consistent with more efficient bacterial killing by Ly6B.2+ myeloid cells and macrophages from WSX-1-deficient compared to wild-type neonates. Live animal imaging further supported a more severe and disseminated infection in WT neonates. This is the first report to describe the impact of elevated early life IL-27 on the host response in neonates while also defining the cell and tissue sources of cytokine. IL-27 is frequently associated with suppressed inflammation. In contrast, our findings demonstrate that IL-27 promotes inflammation during neonatal sepsis by directly compromising control of bacteria that drive the inflammatory response. Collectively, our results suggest that IL-27 represents a therapeutic target to limit susceptibility and improve infectious outcomes in neonatal sepsis.IMPORTANCEA number of differences in the neonatal immune response compared with adults have been well described. However, a mechanistic understanding of what needs to be overcome in the neonate to generate a more protective immune response during acute bacterial infection has been limited. The work described here helps fill the gap of what is necessary to overcome in order to achieve improved host response to infection. To further the novelty, IL-27 has not previously been attributed to dysfunction or deficiency in neonatal immunity. Our results enhance the understanding of IL-27 biology in the neonatal population while providing evidence that elevated IL-27 levels limit a protective immune response and are detrimental during neonatal sepsis. Strategies aimed at targeting circulating IL-27 concentrations early in life have the potential to improve control of bacterial infection in neonates.

scholarly journals Deletion of mouseSetd4promotes the recovery of hematopoietic failure

2019 ◽  
Author(s):  
Xing Feng ◽  
Huimei Lu ◽  
Jingyin Yue ◽  
Megha Shettigar ◽  
Jingmei Liu ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Progenitor Cells ◽  
Whole Body ◽  
List Type ◽  
Bone Marrow Niche ◽  
Hematopoietic Stem ◽  
Adult Mice ◽  
Bm Niche ◽  
Deficient Mice

AbstractAcquired hematopoietic failure is commonly caused by therapeutic and accidental exposure to toxic agents to the bone marrow (BM). Efficient recovery from the BM failure is not only dictated by the intrinsic sensitivity and proliferation capacity of the hematopoietic stem and progenitor cells, but also nourished by the BM environment niche. Identification of genetic factors that improve the recovery from hematopoietic failure is essential. Vertebrate SETD4 is a poorly characterized, putative non-histone methyl-transferase whose physiological substrates have not yet been fully identified. By inducingSetd4deletion in adult mice, we found that loss ofSetd4improved the survival of whole body irradiation induced BM failure. This was associated with improved recoveries of long-term and short-term hematopoietic stem cells (HSC), and early progenitor cells. BM transplantation analyses surprisingly showed that the improved recovery was not due to a radiation resistance of theSetd4deficient HSC, but thatSetd4deficient HSC were actually more sensitive to radiation. However, theSetd4deficient mice were better recipients for allogeneic HSC transplantation. Furthermore, there was an enhanced splenic erythropoiesis inSetd4deficient mice. These findings not only revealed a previously unrecognized role of theSetd4as a unique modulator of hematopoiesis, but also underscored the critical role of the BM niche in the recovery of hematopoietic failure. These studies also implicatedSetd4as a potential target for therapeutic inhibition to improve the conditioning of the BM niche prior to allogeneic transplantation.Key pointsDeletion ofSetd4in adult mice improved the survival from hematopoietic failure.Setd4deficiency sensitized HSCs to radiation, but improved bone marrow environment niche.The study suggests that SETD4 as a potential inhibitory target to improve bone marrow niche function for recovery of bone marrow failure.

Ott1(Rbm15) Is Essential for Pre-B Differentiation and Has an Inhibitory Role in Myeloid and Megakaryocytic Lineages.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 784-784
Author(s):  
Glen D. Raffel ◽  
Thomas Mercher ◽  
Hirokazu Shigematsu ◽  
Ifor R. Williams ◽  
Dana E. Cullen ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cell Fate ◽  
B Lymphopoiesis ◽  
Rna Recognition Motifs ◽  
Adult Mice ◽  
Conditional Allele ◽  
Physiologic Function ◽  
Negative Role ◽  
Recognition Motifs

Abstract OTT1(RBM15) is a putative transcriptional repressor related to the spen/Mint/SHARP family of proteins which was originally identified as the 5′ translocation partner of the MAL(MKL1) gene in t(1;22)(p13;q13) infant acute megakaryocytic leukemia (AMKL). OTT1 contains RNA recognition motifs (RRMs) and a transactivation/repression spen paralog and ortholog (SPOC) homology domain however no physiologic function has yet been attributed to it. To define the role of OTT1 in hematopoiesis and help gain an understanding of potential dysregulated pathways in t(1;22) AMKL, a conditional allele of Ott1 was generated in mice. Germline deletion of Ott1 was early embryonic lethal, however, deletion in adult mice utilizing the Mx1-Cre transgene affected multiple lineages within the hematopoietic compartment. Deletion of Ott1 caused a loss of peripheral B cells as a result of block in pro/pre-B differentiation. An expansion myeloid cells was seen in the spleen and bone marrow and increased numbers of myeloid CFU were detected in the bone marrow. Progenitor analysis demonstrated in increase in Lin−Sca-1+c-Kit+ (LSK) cells with an altered clonogenicity shifting towards granulocytic cell fate. Finally, increased numbers of megakaryocytes were found in the bone marrow and spleen suggesting a negative role for Ott1 in megakaryocytic proliferation/survival. These data indicate a requirement for Ott1 in B lymphopoiesis and inhibitory roles within the myeloid, megakaryocytic and progenitor compartments. Accordingly, the ability of Ott1 to affect hematopoietic cell fate and expansion within multiple lineages including megakaryocytes may underlie the mechanism of OTT1-MAL-mediated leukemogenesis.

scholarly journals Citrullinated Histone H3 Mediates Sepsis-Induced Lung Injury Through Activating Caspase-1 Dependent Inflammasome Pathway

2021 ◽  
Vol 12 ◽  
Author(s):  
Yuzi Tian ◽  
Patrick Li ◽  
Zhenyu Wu ◽  
Qiufang Deng ◽  
Baihong Pan ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Lung Injury ◽  
Host Response ◽  
Distress Syndrome ◽  
Histone H3 ◽  
Caspase 1 ◽  
Sepsis Model ◽  
Important Mediator ◽  
Life Threatening

Sepsis is a life-threatening organ dysfunction caused by dysregulated host response to infection that often results in acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). An emerging mechanism of sepsis-induced ARDS involves neutrophils/macrophages undergoing cell death, releasing nuclear histones to cause tissue damage that exacerbates pulmonary injury. While published studies focus on unmodified histones, little is known about the role of citrullinated histone H3 (CitH3) in the pathogenesis of sepsis and ALI. In this study, we found that levels of CitH3 were elevated in the patients with sepsis-induced ARDS and correlated to PaO2/FiO2 in septic patients. Systematic administration of CitH3 peptide in mice provoked Caspase-1 activation in the lung tissue and caused ALI. Neutralization of CitH3 with monoclonal antibody improved survival and attenuated ALI in a mouse sepsis model. Furthermore, we demonstrated that CitH3 induces ALI through activating Caspase-1 dependent inflammasome in bone marrow derived macrophages and bone marrow derived dendritic cells. Our study suggests that CitH3 is an important mediator of inflammation and mortality during sepsis-induced ALI.

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