دورية أكاديمية
Cell-free hemoglobin triggers macrophage cytokine production via TLR4 and MyD88.
| العنوان: | Cell-free hemoglobin triggers macrophage cytokine production via TLR4 and MyD88. |
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| المؤلفون: | Schaaf KR; Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, United States.; Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, United States., Landstreet SR; Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, United States., Pugazenthi S; Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, United States., Qian EY; Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, United States., Putz ND; Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, United States., Siderova T; Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, United States., Owen AM; Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, Tennessee, United States., Bohannon JK; Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, United States.; Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, Tennessee, United States., Ware LB; Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, United States.; Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, United States., Bastarache JA; Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, United States.; Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, United States.; Department of Cell and Molecular Biology, Vanderbilt University, Nashville, Tennessee, United States., Shaver CM; Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, United States. |
| المصدر: | American journal of physiology. Lung cellular and molecular physiology [Am J Physiol Lung Cell Mol Physiol] 2024 Jan 01; Vol. 326 (1), pp. L29-L38. Date of Electronic Publication: 2023 Nov 22. |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't; Research Support, N.I.H., Extramural |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Physiological Society Country of Publication: United States NLM ID: 100901229 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1522-1504 (Electronic) Linking ISSN: 10400605 NLM ISO Abbreviation: Am J Physiol Lung Cell Mol Physiol Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Bethesda, MD : American Physiological Society, c1989- |
| مواضيع طبية MeSH: | Acute Lung Injury*/metabolism , Respiratory Distress Syndrome*/complications, Humans ; Mice ; Animals ; Toll-Like Receptor 4/metabolism ; Myeloid Differentiation Factor 88/metabolism ; Interleukin-6/metabolism ; Adaptor Proteins, Signal Transducing/metabolism ; Cytokines/metabolism ; Macrophages/metabolism ; Inflammation/etiology ; Tumor Necrosis Factor-alpha/metabolism ; Hemoglobins/metabolism ; Mice, Inbred C57BL ; Mice, Knockout |
| مستخلص: | Cell-free hemoglobin (CFH) is elevated in the airspace of patients with acute respiratory distress syndrome (ARDS) and is sufficient to cause acute lung injury in a murine model. However, the pathways through which CFH causes lung injury are not well understood. Toll-like receptor 4 (TLR4) is a mediator of inflammation after detection of damage- and pathogen-associated molecular patterns. We hypothesized that TLR4 signaling mediates the proinflammatory effects of CFH in the airspace. After intratracheal CFH, BALBc mice deficient in TLR4 had reduced inflammatory cell influx into the airspace [bronchoalveolar lavage (BAL) cell counts, median TLR4 knockout (KO): 0.8 × 10 4 /mL [IQR 0.4-1.2 × 10 4 /mL], wild-type (WT): 3.0 × 10 4 /mL [2.2-4.0 × 10 4 /mL], P < 0.001] and attenuated lung permeability (BAL protein, TLR4KO: 289 µg/mL [236-320], WT: 488 µg/mL [422-536], P < 0.001). These mice also had attenuated production of interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α in the airspace. C57Bl/6 mice lacking TLR4 on myeloid cells only (LysM.Cre +/- TLR4 fl/fl ) had reduced cytokine production in the airspace after CFH, without attenuation of lung permeability. In vitro studies confirm that WT primary murine alveolar macrophages exposed to CFH (0.01-1 mg/mL) had dose-dependent increases in IL-6, IL-1 β, CXC motif chemokine ligand 1 (CXCL-1), TNF-α, and IL-10 ( P < 0.001). Murine MH-S alveolar-like macrophages show TLR4-dependent expression of IL-1β, IL-6, and CXCL-1 in response to CFH. Primary alveolar macrophages from mice lacking TLR4 adaptor proteins myeloid differentiation primary response 88 (MyD88) or TIR-domain-containing adapter-inducing interferon-β (TRIF) revealed that MyD88KO macrophages had 71-96% reduction in CFH-dependent proinflammatory cytokine production ( P < 0.001), whereas macrophages from TRIFKO mice had variable changes in cytokine responses. These data demonstrate that myeloid TLR4 signaling through MyD88 is a key regulator of airspace inflammation in response to CFH. NEW & NOTEWORTHY Cell-free hemoglobin (CFH) is elevated in the airspace of most patients with acute respiratory distress syndrome and causes severe inflammation. Here, we identify that CFH contributes to macrophage-induced cytokine production via Toll-like receptor 4 (TLR4) and myeloid differentiation primary response 88 (MyD88) signaling. These data increase our knowledge of the mechanisms through which CFH contributes to lung injury and may inform development of targeted therapeutics to attenuate inflammation. |
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| معلومات مُعتمدة: | R01 HL158906 United States HL NHLBI NIH HHS; K08 HL136888 United States HL NHLBI NIH HHS; R01 HL160551 United States HL NHLBI NIH HHS; UL1 TR002243 United States TR NCATS NIH HHS; R01 HL164937 United States HL NHLBI NIH HHS; R35 GM141927 United States GM NIGMS NIH HHS; I01 BX002288 United States BX BLRD VA; R01 HL126671 United States HL NHLBI NIH HHS; R35 HL150783 United States HL NHLBI NIH HHS |
| فهرسة مساهمة: | Keywords: TLR4; acute lung injury; cell-free hemoglobin; inflammation; macrophages |
| المشرفين على المادة: | 0 (Toll-Like Receptor 4) 0 (Myeloid Differentiation Factor 88) 0 (Interleukin-6) 0 (Adaptor Proteins, Signal Transducing) 0 (Cytokines) 0 (Tumor Necrosis Factor-alpha) 0 (Hemoglobins) 0 (TLR4 protein, human) |
| تواريخ الأحداث: | Date Created: 20231122 Date Completed: 20231222 Latest Revision: 20240728 |
| رمز التحديث: | 20240728 |
| مُعرف محوري في PubMed: | PMC11279742 |
| DOI: | 10.1152/ajplung.00123.2023 |
| PMID: | 37991487 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1522-1504 |
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| DOI: | 10.1152/ajplung.00123.2023 |