Chlamydia evasion of neutrophil host defense results in NLRP3 dependent myeloid-mediated sterile inflammation through the purinergic P2X7 receptor.
Adenosine Triphosphate
/ immunology
Animals
Cells, Cultured
Chlamydia
/ immunology
Chlamydia Infections
/ immunology
Disease Models, Animal
Female
HeLa Cells
Host-Pathogen Interactions
/ immunology
Humans
Immune Evasion
/ immunology
Inflammation
/ immunology
Macrophages
/ immunology
Mice, Inbred C57BL
Mice, Knockout
Myeloid Cells
/ immunology
NLR Family, Pyrin Domain-Containing 3 Protein
/ immunology
Neutrophils
/ immunology
Receptors, Purinergic P2X7
/ genetics
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
15 09 2021
15 09 2021
Historique:
received:
31
08
2020
accepted:
27
08
2021
entrez:
16
9
2021
pubmed:
17
9
2021
medline:
21
10
2021
Statut:
epublish
Résumé
Chlamydia trachomatis infection causes severe inflammatory disease resulting in blindness and infertility. The pathophysiology of these diseases remains elusive but myeloid cell-associated inflammation has been implicated. Here we show NLRP3 inflammasome activation is essential for driving a macrophage-associated endometritis resulting in infertility by using a female mouse genital tract chlamydial infection model. We find the chlamydial parasitophorous vacuole protein CT135 triggers NLRP3 inflammasome activation via TLR2/MyD88 signaling as a pathogenic strategy to evade neutrophil host defense. Paradoxically, a consequence of CT135 mediated neutrophil killing results in a submucosal macrophage-associated endometritis driven by ATP/P2X7R induced NLRP3 inflammasome activation. Importantly, macrophage-associated immunopathology occurs independent of macrophage infection. We show chlamydial infection of neutrophils and epithelial cells produce elevated levels of extracellular ATP. We propose this source of ATP serves as a DAMP to activate submucosal macrophage NLRP3 inflammasome that drive damaging immunopathology. These findings offer a paradigm of sterile inflammation in infectious disease pathogenesis.
Identifiants
pubmed: 34526512
doi: 10.1038/s41467-021-25749-3
pii: 10.1038/s41467-021-25749-3
pmc: PMC8443728
doi:
Substances chimiques
NLR Family, Pyrin Domain-Containing 3 Protein
0
Receptors, Purinergic P2X7
0
Adenosine Triphosphate
8L70Q75FXE
Types de publication
Journal Article
Research Support, N.I.H., Intramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
5454Informations de copyright
© 2021. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.
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