title: STAT3-dependent CXC chemokine formation and neutrophil migration in streptococcal M1 protein-induced acute lung inflammation.
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.
authors.affiliation: Department of Clinical Sciences, Section for Surgery, Lund University, Malmö, Sweden and.
authors.forename: Songen
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Clinical Sciences, Section for Surgery, Lund University, Malmö, Sweden and.
authors.forename: Rundk
authors.initials: R
authors.lastname: Hwaiz
authors.affiliation: Department of Clinical Sciences, Section for Surgery, Lund University, Malmö, Sweden and.
authors.forename: Lingtao
authors.initials: L
authors.lastname: Luo
authors.affiliation: Division of Infection Medicine, Lund University, Lund, Sweden.
authors.forename: Heiko
authors.initials: H
authors.lastname: Herwald
authors.affiliation: Department of Clinical Sciences, Section for Surgery, Lund University, Malmö, Sweden and henrik.thorlacius@med.lu.se.
authors.forename: Henrik
authors.initials: H
authors.lastname: Thorlacius
mesh_terms: D055371:Acute Lung Injury / Q000276:immunology*; D000818:Animals; D000942:Antigens, Bacterial / Q000276:immunology*; D001425:Bacterial Outer Membrane Proteins / Q000276:immunology*; D002352:Carrier Proteins / Q000276:immunology*; D002465:Cell Movement; D024243:HMGB1 Protein / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D008168:Lung / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016177:Macrophage-1 Antigen / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D020556:Neutrophil Infiltration; D009504:Neutrophils / Q000502:physiology*; D050796:STAT3 Transcription Factor / Q000502:physiology*
chemical_list: D000942:Antigens, Bacterial; D001425:Bacterial Outer Membrane Proteins; D002352:Carrier Proteins; D024243:HMGB1 Protein; C582808:HMGB1 protein, mouse; D015850:Interleukin-6; D016177:Macrophage-1 Antigen; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; C014689:streptococcal M protein
keywords: adhesion; inflammation; leukocytes; sepsis