TNF-related apoptosis-inducing ligand (TRAIL) exerts therapeutic efficacy for the treatment of pneumococcal pneumonia in mice.
Apoptotic death of alveolar macrophages observed during lung infection with Streptococcus pneumoniae is thought to limit overwhelming lung inflammation in response to bacterial challenge. However, the underlying apoptotic death mechanism has not been defined. Here, we examined the role of the TNF superfamily member TNF-related apoptosis-inducing ligand (TRAIL) in S. pneumoniae-induced macrophage apoptosis, and investigated the potential benefit of TRAIL-based therapy during pneumococcal pneumonia in mice. Compared with WT mice, Trail(-/-) mice demonstrated significantly decreased lung bacterial clearance and survival in response to S. pneumoniae, which was accompanied by significantly reduced apoptosis and caspase 3 cleavage but rather increased necrosis in alveolar macrophages. In WT mice, neutrophils were identified as a major source of intraalveolar released TRAIL, and their depletion led to a shift from apoptosis toward necrosis as the dominant mechanism of alveolar macrophage cell death in pneumococcal pneumonia. Therapeutic application of TRAIL or agonistic anti-DR5 mAb (MD5-1) dramatically improved survival of S. pneumoniae-infected WT mice. Most importantly, neutropenic mice lacking neutrophil-derived TRAIL were protected from lethal pneumonia by MD5-1 therapy. We have identified a previously unrecognized mechanism by which neutrophil-derived TRAIL induces apoptosis of DR5-expressing macrophages, thus promoting early bacterial killing in pneumococcal pneumonia. TRAIL-based therapy in neutropenic hosts may represent a novel antibacterial treatment option.
Department of Experimental Pneumology and 2 Clinic for Pneumology, Hannover School of Medicine, Hannover 30625, Germany.
Kathrin
K
Steinwede
Stefanie
S
Henken
Jennifer
J
Bohling
Regina
R
Maus
Bianca
B
Ueberberg
Christina
C
Brumshagen
Erik L
EL
Brincks
Thomas S
TS
Griffith
Tobias
T
Welte
Ulrich A
UA
Maus
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D054884:Host-Pathogen Interactions / Q000187:drug effects; D008168:Lung / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009336:Necrosis; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011018:Pneumonia, Pneumococcal / Q000188:drug therapy* / Q000235:genetics / Q000382:microbiology; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000276:immunology / Q000378:metabolism; D013296:Streptococcus pneumoniae / Q000187:drug effects* / Q000502:physiology; D016019:Survival Analysis; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D016896:Treatment Outcome
D000911:Antibodies, Monoclonal; D016207:Cytokines; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; D053148:Caspase 3