S-Nitrosylation of α1-Antitrypsin Triggers Macrophages Toward Inflammatory Phenotype and Enhances Intra-Cellular Bacteria Elimination.

Authors:
Ziv Kaner
Ziv Kaner
Ben-Gurion University of the Negev
Israel
Rotem Engelman
Rotem Engelman
Technion-Israel Institute of Technology
Israel
Peleg Rider
Peleg Rider
Ben-Gurion University of the Negev
Israel
David Greenberg
David Greenberg
Ben-Gurion University of the Negev
Israel
Moran Benhar
Moran Benhar
Duke University Medical Center
United States
Eli C Lewis
Eli C Lewis
Ben-Gurion University of the Negev
Israel

Front Immunol 2019 2;10:590. Epub 2019 Apr 2.

Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.

Human α1-antitrypsin (hAAT) is a circulating anti-inflammatory serine-protease inhibitor that rises during acute phase responses. , hAAT reduces bacterial load, without directly inhibiting bacterial growth. In conditions of excess nitric-oxide (NO), hAAT undergoes S-nitrosylation (S-NO-hAAT) and gains antibacterial capacity. The impact of S-NO-hAAT on immune cells has yet to be explored. Study the effects of S-NO-hAAT on immune cells during bacterial infection. Clinical-grade hAAT was S-nitrosylated and then compared to unmodified hAAT, functionally, and structurally. Intracellular bacterial clearance by THP-1 macrophages was assessed using live . Murine peritoneal macrophages were examined, and signaling pathways were evaluated. S-NO-hAAT was also investigated after blocking free mambranal cysteine residues on cells. S-NO-hAAT (27.5 uM) enhances intracellular bacteria elimination by immunocytes (up to 1-log reduction). S-NO-hAAT causes resting macrophages to exhibit a pro-inflammatory and antibacterial phenotype, including release of inflammatory cytokines and induction of inducible nitric oxide synthase (iNOS) and TLR2. These pro-inflammatory effects are dependent upon cell surface thiols and activation of MAPK pathways. hAAT duality appears to be context-specific, involving S-nitrosylation in a nitric oxide rich environment. Our results suggest that S-nitrosylation facilitates the antibacterial activity of hAAT by promoting its ability to activate innate immune cells. This pro-inflammatory effect may involve transferring of nitric oxide from S-NO-hAAT to a free cysteine residue on cellular targets.

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Source
http://dx.doi.org/10.3389/fimmu.2019.00590DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6454134PMC
April 2019
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