Serum amyloid A3 confers protection against acute lung injury inPseudomonas aeruginosa-infected mice

Abstract

Pseudomonas aeruginosa is a gram-negative bacterium associated with serious illnesses, including ventilator-associated pneumonia and various sepsis syndromes in humans. Understanding the host immune mechanisms against P. aeruginosa is, therefore, of clinical importance. The present study identified serum amyloid A3 (SAA3) as being highly inducible in mouse bronchial epithelium following P. aeruginosa infection. Genetic deletion of Saa3 rendered mice more susceptible to P. aeruginosa infection with decreased neutrophil superoxide anion production, and ex vivo treatment of mouse neutrophils with recombinant SAA3 restored the ability of neutrophils to produce superoxide anions. The SAA3-deficient mice showed exacerbated inflammatory responses, which was characterized by pronounced neutrophil infiltration, elevated expression of TNF-α, KC/CXCL1, and MIP-2/CXCL2 in bronchoalveolar lavage fluid (BALF), and increased lung microvascular permeability compared with their wild-type littermates. BALF neutrophils from Saa3 knockout mice exhibited reduced superoxide anion production compared with neutrophils from wild-type mice. Adoptive transfer of SAA3-treated neutrophils to Saa3 knockout mice ameliorated P. aeruginosa-induced acute lung injury. These findings demonstrate that SAA3 not only serves as a biomarker for infection and inflammation, but also plays a protective role against P. aeruginosa infection-induced lung injury in part through augmentation of neutrophil bactericidal functions.

The turning away of serum amyloid A biological activities and receptor usage

“…Through the use of animal models, several studies have demonstrated upregulated expression of SAA upon bacterial infection. 30,31 Whether or not SAA expression occurs in vivo directly in response to TLR ligands or via upregulated inflammatory cytokines is unknown. Nevertheless, in vitro studies have demonstrated the expression of SAA by human hepatocytes in response to the bacterial product LPS.…”

Liver-Dependent Lung Remodeling during Systemic Inflammation Shapes Responses to Secondary Infection

“…For instance, mice lacking the gene encoding serum amyloid P (Apcs) are susceptible to pneumonia, providing an important example whereby a specific factor contributes to lung immunity (83). Similar results have been reported for other APPspecific knockout mice (86,87), but this strategy neither accounts for baseline APP concentrations nor does it specify the importance of hepatocytes as the origin of gene expression. In all likelihood, the benefits of STAT3-driven hepatocyte activity observed in our prior and current studies are due to integrated contributions from multiple factors that alter lung immunity in a complex and coordinated fashion.…”

Phenotypes, Lung Microbiota and Cytokine Responses in Pneumonia After Hematopoietic Stem Cell Transplantation

“…PA and MHV infections were performed as previously described. 26 , 27 For the IL-6 treatment, mice were treated intranasally with mouse recombinant IL-6 protein (R&D, Minneapolis, MN) at a dosage of 25ug per mouse, diluted with PBS with 0.1% BSA to 50 µL, intranasal inoculated on day 4, 5, 6, 7 post infection. 28 BALF samples and lung tissues were harvested at day 8 post-infection.…”