S-nitrosylation of α1-antitrypsin triggers macrophages toward inflammatory phenotype and enhances intra-cellular bacteria elimination

Ziv Kaner, Rotem Engelman, Ronen Schuster, Peleg Rider, David Greenberg, Yossef Av-Gay, Moran Benhar, Eli C. Lewis

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

Background: Human α1-antitrypsin (hAAT) is a circulating anti-inflammatory serine-protease inhibitor that rises during acute phase responses. in vivo, 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. Aim: Study the effects of S-NO-hAAT on immune cells during bacterial infection. Methods: 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 Salmonella typhi. Murine peritoneal macrophages were examined, and signaling pathways were evaluated. S-NO-hAAT was also investigated after blocking free mambranal cysteine residues on cells. Results: 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. Conclusions: 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 proinflammatory effect may involve transferring of nitric oxide from SNO-hAAT to a free cysteine residue on cellular targets.

Original languageEnglish
Article number590
JournalFrontiers in Immunology
Volume10
Issue numberAPR
DOIs
StatePublished - 1 Jan 2019

Keywords

  • Acute phase response
  • Cell activation
  • Cytokines
  • Infection
  • Inflammation
  • Nitric oxide
  • Protease

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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