Thrombospondin-1 Restricts Interleukin-36γ-Mediated Neutrophilic Inflammation during Pseudomonas aeruginosa Pulmonary Infection
| Autor: | Tolani F. Olonisakin, Chunbin Zou, Mei Hulver, William Bain, Joel A. Ybe, Yanyan Qu, Jill Zupetic, Hernán F. Peñaloza, Michael W. Newstead, Jonathan K. Alder, Zeyu Xiong, Rick van der Geest, Janet S. Lee, Theodore J. Standiford |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Male
Proteases Neutrophils medicine.medical_treatment Inflammation Microbiology Proinflammatory cytokine Thrombospondin 1 Mice 03 medical and health sciences 0302 clinical medicine Virology medicine Extracellular Animals Pseudomonas Infections thrombospondin-1 Lung 030304 developmental biology Cathepsin S Mice Knockout 0303 health sciences IL-36γ biology Chemistry Matricellular protein QR1-502 Mice Inbred C57BL Cytokine Neutrophil Infiltration Neutrophil elastase Host-Pathogen Interactions Pseudomonas aeruginosa biology.protein Female medicine.symptom proteolytic environment Interleukin-1 Research Article 030215 immunology |
| Zdroj: | mBio, Vol 12, Iss 2 (2021) mBio |
| ISSN: | 2150-7511 |
| Popis: | Pseudomonas aeruginosa pulmonary infection can lead to exaggerated neutrophilic inflammation and tissue destruction, yet host factors that regulate the neutrophilic response is not fully known. IL-36γ is a proinflammatory cytokine that dramatically increases in bioactivity following N-terminal processing by proteases. Interleukin-36γ (IL-36γ), a member of the IL-1 cytokine superfamily, amplifies lung inflammation and impairs host defense during acute pulmonary Pseudomonas aeruginosa infection. To be fully active, IL-36γ is cleaved at its N-terminal region by proteases such as neutrophil elastase (NE) and cathepsin S (CatS). However, it remains unclear whether limiting extracellular proteolysis restrains the inflammatory cascade triggered by IL-36γ during P. aeruginosa infection. Thrombospondin-1 (TSP-1) is a matricellular protein with inhibitory activity against NE and the pathogen-secreted Pseudomonas elastase LasB—both proteases implicated in amplifying inflammation. We hypothesized that TSP-1 tempers the inflammatory response during lung P. aeruginosa infection by inhibiting the proteolytic environment required for IL-36γ activation. Compared to wild-type (WT) mice, TSP-1-deficient (Thbs1−/−) mice exhibited a hyperinflammatory response in the lungs during P. aeruginosa infection, with increased cytokine production and an unrestrained extracellular proteolytic environment characterized by higher free NE and LasB, but not CatS activity. LasB cleaved IL-36γ proximally to M19 at a cleavage site distinct from those generated by NE and CatS, which cleave IL-36γ proximally to Y16 and S18, respectively. N-terminal truncation experiments in silico predicted that the M19 and the S18 isoforms bind the IL-36R complex almost identically. IL-36γ neutralization ameliorated the hyperinflammatory response and improved lung immunity in Thbs1−/− mice during P. aeruginosa infection. Moreover, administration of cleaved IL-36γ induced cytokine production and neutrophil recruitment and activation that was accentuated in Thbs1−/− mice lungs. Collectively, our data show that TSP-1 regulates lung neutrophilic inflammation and facilitates host defense by restraining the extracellular proteolytic environment required for IL-36γ activation. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|