دورية أكاديمية
Placental HTRA1 cleaves α1-antitrypsin to generate a NET-inhibitory peptide.
| العنوان: | Placental HTRA1 cleaves α1-antitrypsin to generate a NET-inhibitory peptide. |
|---|---|
| المؤلفون: | Campbell RA; University of Utah Molecular Medicine Program, Salt Lake City, UT; and.; Department of Internal Medicine., Campbell HD; Department of Obstetrics and Gynecology., Bircher JS; Department of Pediatrics, and., de Araujo CV; University of Utah Molecular Medicine Program, Salt Lake City, UT; and., Denorme F; University of Utah Molecular Medicine Program, Salt Lake City, UT; and., Crandell JL; University of Utah Molecular Medicine Program, Salt Lake City, UT; and., Rustad JL; University of Utah Molecular Medicine Program, Salt Lake City, UT; and., Monts J; Flow Cytometry Core, University of Utah, Salt Lake City, UT., Cody MJ; University of Utah Molecular Medicine Program, Salt Lake City, UT; and.; Department of Pediatrics, and., Kosaka Y; University of Utah Molecular Medicine Program, Salt Lake City, UT; and., Yost CC; University of Utah Molecular Medicine Program, Salt Lake City, UT; and.; Department of Pediatrics, and. |
| المصدر: | Blood [Blood] 2021 Sep 16; Vol. 138 (11), pp. 977-988. |
| نوع المنشور: | Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: Elsevier Country of Publication: United States NLM ID: 7603509 Publication Model: Print Cited Medium: Internet ISSN: 1528-0020 (Electronic) Linking ISSN: 00064971 NLM ISO Abbreviation: Blood Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: 2021- : [New York] : Elsevier Original Publication: New York, Grune & Stratton [etc.] |
| مواضيع طبية MeSH: | Extracellular Traps/*metabolism , High-Temperature Requirement A Serine Peptidase 1/*metabolism , Placenta/*metabolism , alpha 1-Antitrypsin/*metabolism, Animals ; Female ; Humans ; Mice, Inbred C57BL ; Pregnancy ; Proteolysis ; Mice |
| مستخلص: | Neutrophil extracellular traps (NETs) are important components of innate immunity. Neonatal neutrophils (polymorphonuclear leukocytes [PMNs]) fail to form NETs due to circulating NET-inhibitory peptides (NIPs), cleavage fragments of α1-antitrypsin (A1AT). How fetal and neonatal blood NIPs are generated remains unknown, however. The placenta expresses high-temperature requirement serine protease A1 (HTRA1) during fetal development, which can cleave A1AT. We hypothesized that placentally expressed HTRA1 regulates the formation of NIPs and that NET competency changed in PMNs isolated from neonatal HTRA1 knockout mice (HTRA1-/-). We found that umbilical cord blood plasma has elevated HTRA1 levels compared with adult plasma and that recombinant and placenta-eluted HTRA1 cleaves A1AT to generate an A1AT cleavage fragment (A1ATM383S-CF) of molecular weight similar to previously identified NIPs that block NET formation by adult neutrophils. We showed that neonatal mouse pup plasma contains A1AT fragments that inhibit NET formation by PMNs isolated from adult mice, indicating that NIP generation during gestation is conserved across species. Lipopolysaccharide-stimulated PMNs isolated from HTRA1+/+ littermate control pups exhibit delayed NET formation after birth. However, plasma from HTRA1-/- pups had no detectable NIPs, and PMNs from HTRA1-/- pups became NET competent earlier after birth compared with HTRA1+/+ littermate controls. Finally, in the cecal slurry model of neonatal sepsis, A1ATM383S-CF improved survival in C57BL/6 pups by preventing pathogenic NET formation. Our data indicate that placentally expressed HTRA1 is a serine protease that cleaves A1AT in utero to generate NIPs that regulate NET formation by human and mouse PMNs. (© 2021 by The American Society of Hematology.) |
| التعليقات: | Comment in: Blood. 2021 Sep 16;138(11):920-921. (PMID: 34529018) |
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| معلومات مُعتمدة: | U24 NS107228 United States NS NINDS NIH HHS; UL1 TR002538 United States TR NCATS NIH HHS; S10 OD026959 United States OD NIH HHS; R01 HD093826 United States HD NICHD NIH HHS; K01 AG059892 United States AG NIA NIH HHS; R33 HL141783 United States HL NHLBI NIH HHS |
| المشرفين على المادة: | 0 (SERPINA1 protein, human) 0 (Serpina1a protein, mouse) 0 (alpha 1-Antitrypsin) EC 3.4.21.- (High-Temperature Requirement A Serine Peptidase 1) EC 3.4.21.- (HTRA1 protein, human) EC 3.4.21.- (HtrA1 protein, mouse) |
| تواريخ الأحداث: | Date Created: 20210630 Date Completed: 20211210 Latest Revision: 20240226 |
| رمز التحديث: | 20240226 |
| مُعرف محوري في PubMed: | PMC9069473 |
| DOI: | 10.1182/blood.2020009021 |
| PMID: | 34192300 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1528-0020 |
|---|---|
| DOI: | 10.1182/blood.2020009021 |