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Published on: December 15, 2014
STAT3-dependent CXC chemokine formation and neutrophil migration in streptococcal M1 protein-induced acute lung
Songen Zhang1, Rundk Hwaiz1, Lingtao Luo1
1Department of Clinical Sciences, Section for Surgery, Lund University, Malmö, Sweden and.
Abstract:
Streptococcus pyogenes cause infections ranging from mild pharyngitis to severe streptococcal toxic shock syndrome (STSS). The M1 serotype of Streptococcus pyogenes is most frequently associated with STSS. Herein, it was hypothesized that STAT3 signaling might be involved in M1 protein-evoked lung inflammation. The STAT3 inhibitor, S3I-201, was administered to male C57Bl/6 mice before iv challenge with M1 protein. Bronchoalveolar fluid and lung tissue were harvested for quantification of STAT3 activity, neutrophil recruitment, edema, and CXC chemokine formation. Neutrophil expression of Mac-1 was quantified by use of flow cytometry. Levels of IL-6 and HMGB1 were determined in plasma. CXCL2-induced neutrophil chemotaxis was studied in vitro. Administration of S3I-201 markedly reduced M1 protein-provoked STAT3 activity, neutrophil recruitment, edema formation, and inflammatory changes in the lung. In addition, M1 protein significantly increased Mac-1 expression on neutrophils and CXC chemokine levels in the lung. Treatment with S3I-201 had no effect on M1 protein-induced expression of Mac-1 on neutrophils. In contrast, inhibition of STAT3 activity greatly reduced M1 protein-induced formation of CXC chemokines in the lung. Interestingly, STAT3 inhibition markedly decreased plasma levels of IL-6 and HMGB1 in animals exposed to M1 protein. Moreover, we found that S3I-201 abolished CXCL2-induced neutrophil migration in vitro. In conclusion, these novel findings indicate that STAT3 signaling plays a key role in mediating CXC chemokine production and neutrophil infiltration in M1 protein-induced acute lung inflammation.
Insights
STAT3 signaling is crucial in M1 protein-induced lung inflammation. Inhibiting STAT3 reduces neutrophil recruitment and chemokine production, offering potential therapeutic targets for Streptococcus pyogenes infections.
Area of Science:
- Immunology
- Microbiology
- Pulmonology
Background:
- Streptococcus pyogenes, particularly the M1 serotype, is linked to severe infections like streptococcal toxic shock syndrome (STSS).
- Lung inflammation is a significant complication of M1 serotype Streptococcus pyogenes infections.
- The precise molecular mechanisms driving M1 protein-induced lung inflammation require further elucidation.
Purpose of the Study:
- To investigate the role of STAT3 (Signal Transducer and Activator of Transcription 3) signaling in M1 protein-induced lung inflammation.
- To evaluate the therapeutic potential of a STAT3 inhibitor (S3I-201) in mitigating M1 protein-induced lung inflammation.
Main Methods:
- Male C57Bl/6 mice were treated with the STAT3 inhibitor S3I-201 prior to intravenous challenge with M1 protein.
- Analysis of bronchoalveolar fluid and lung tissue for STAT3 activity, neutrophil infiltration, edema, and CXC chemokine levels.
- Flow cytometry was used to quantify Mac-1 expression on neutrophils; IL-6 and HMGB1 levels were measured in plasma; in vitro neutrophil chemotaxis was assessed.
Main Results:
- S3I-201 treatment significantly reduced M1 protein-induced STAT3 activity, neutrophil recruitment, edema, and overall lung inflammation.
- M1 protein increased neutrophil Mac-1 expression and CXC chemokine levels, while STAT3 inhibition primarily reduced chemokine formation and neutrophil migration.
- STAT3 inhibition notably decreased plasma levels of IL-6 and HMGB1 and abolished CXCL2-induced neutrophil migration in vitro.
Conclusions:
- STAT3 signaling is a key mediator in the pathogenesis of M1 protein-induced acute lung inflammation.
- STAT3 inhibition effectively reduces M1 protein-induced CXC chemokine production and neutrophil infiltration in the lungs.
- Targeting STAT3 signaling represents a promising therapeutic strategy for managing severe Streptococcus pyogenes M1 serotype infections.
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