title: Streptococcal M1 protein triggers chemokine formation, neutrophil infiltration, and lung injury in an NFAT-dependent manner.
abstract: Streptococcus pyogenes of the M1 serotype can cause STSS, which is associated with significant morbidity and mortality. The purpose of the present study was to examine the role of NFAT signaling in M1 protein-induced lung injury. NFAT-luc mice were treated with the NFAT inhibitor A-285222 before administration of the M1 protein. Neutrophil infiltration, edema, and CXC chemokines were quantified in the lung, 4 h after challenge with the M1 protein. Flow cytometry was used to determine Mac-1 expression. Challenge with the M1 protein increased NFAT-dependent transcriptional activity in the lung, spleen, and liver in NFAT-luc mice. Administration of the NFAT inhibitor A-285222 abolished M1 protein-evoked NFAT activation in the lung, spleen, and liver. M1 protein challenge induced neutrophil recruitment, edema, and CXC chemokine production in the lung, as well as up-regulation of Mac-1 on circulating neutrophils. Inhibition of NFAT activity attenuated M1 protein-induced neutrophil infiltration by 77% and edema formation by 50% in the lung. Moreover, administration of A-285222 reduced M1 protein-evoked pulmonary formation of CXC chemokine >80%. In addition, NFAT inhibition decreased M1 protein-triggered Mac-1 up-regulation on neutrophils. These findings indicate that NFAT signaling controls pulmonary infiltration of neutrophils in response to streptococcal M1 protein via formation of CXC chemokines and neutrophil expression of Mac-1. Thus, the targeting of NFAT activity might be a useful way to ameliorate lung injury in streptococcal infections.
authors.affiliation: Sections for *Surgery and Vascular Excitation-Transcription Coupling, Department of Clinical Sciences Malmö, Lund University, Malmö, Sweden; and Department of Clinical Sciences Lund, Section for Clinical and Experimental Infection Medicine, Lund University, Sweden.
authors.forename: Songen
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Sections for *Surgery and Vascular Excitation-Transcription Coupling, Department of Clinical Sciences Malmö, Lund University, Malmö, Sweden; and Department of Clinical Sciences Lund, Section for Clinical and Experimental Infection Medicine, Lund University, Sweden.
authors.forename: Su
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Sections for *Surgery and Vascular Excitation-Transcription Coupling, Department of Clinical Sciences Malmö, Lund University, Malmö, Sweden; and Department of Clinical Sciences Lund, Section for Clinical and Experimental Infection Medicine, Lund University, Sweden.
authors.forename: Eliana
authors.initials: E
authors.lastname: Garcia-Vaz
authors.affiliation: Sections for *Surgery and Vascular Excitation-Transcription Coupling, Department of Clinical Sciences Malmö, Lund University, Malmö, Sweden; and Department of Clinical Sciences Lund, Section for Clinical and Experimental Infection Medicine, Lund University, Sweden.
authors.forename: Heiko
authors.initials: H
authors.lastname: Herwald
authors.affiliation: Sections for *Surgery and Vascular Excitation-Transcription Coupling, Department of Clinical Sciences Malmö, Lund University, Malmö, Sweden; and Department of Clinical Sciences Lund, Section for Clinical and Experimental Infection Medicine, Lund University, Sweden.
authors.forename: Maria F
authors.initials: MF
authors.lastname: Gomez
authors.affiliation: Sections for *Surgery and Vascular Excitation-Transcription Coupling, Department of Clinical Sciences Malmö, Lund University, Malmö, Sweden; and Department of Clinical Sciences Lund, Section for Clinical and Experimental Infection Medicine, Lund University, Sweden henrik.thorlacius@med.lu.se.
authors.forename: Henrik
authors.initials: H
authors.lastname: Thorlacius
mesh_terms: D000818:Animals; D000942:Antigens, Bacterial / Q000008:administration & dosage*; D001425:Bacterial Outer Membrane Proteins / Q000008:administration & dosage*; D002352:Carrier Proteins / Q000008:administration & dosage*; D019743:Chemokines, CXC / Q000235:genetics / Q000276:immunology; D005260:Female; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D054884:Host-Pathogen Interactions / Q000276:immunology*; D007275:Injections, Intravenous; D008099:Liver / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D008156:Luciferases / Q000235:genetics / Q000276:immunology; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D055370:Lung Injury / Q000139:chemically induced / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D016177:Macrophage-1 Antigen / Q000235:genetics / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D050778:NFATC Transcription Factors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology; D020556:Neutrophil Infiltration / Q000187:drug effects; D011654:Pulmonary Edema / Q000139:chemically induced / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D011720:Pyrazoles / Q000494:pharmacology*; D015398:Signal Transduction; D013154:Spleen / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D013297:Streptococcus pyogenes / Q000737:chemistry
chemical_list: C494244:A 285222; D000942:Antigens, Bacterial; D001425:Bacterial Outer Membrane Proteins; D002352:Carrier Proteins; D019743:Chemokines, CXC; D016177:Macrophage-1 Antigen; D050778:NFATC Transcription Factors; D011720:Pyrazoles; C014689:streptococcal M protein; D008156:Luciferases
keywords: infection; leukocytes; migration; sepsis