Loss of suppression of tumorigenicity 2 (ST2) gene reverses sepsis-induced inhibition of lung host defense in mice.
BACKGROUND
After surviving the initial hyperinflammatory phase, patients with sepsis display features consistent with immunosuppression, which renders the host susceptible to nosocomial infections, in particular bacterial pneumonia. Suppression of tumorigenicity 2 (ST2) is a negative regulator of Toll-like receptor signaling implicated in endotoxin tolerance.


OBJECTIVE
The present study sought to determine the role of ST2 in modulating host defense in the lung during sepsis, using a murine model of cecal ligation and puncture (CLP)-induced sepsis followed by a secondary infection with Pseudomonas aeruginosa via the airways.


METHODS
CLP or sham surgery was performed on BALB/c wild-type (WT) and ST2 knockout (KO) mice, and 24 hours later animals were challenged with 10(8) live P. aeruginosa.


RESULTS
CLP mice demonstrated impaired clearance of Pseudomonas from their lungs and reduced pulmonary levels of tumor necrosis factor-α and IL-6 compared with sham mice. After CLP, ST2KO mice with secondary pneumonia displayed a strongly improved survival and a better bacterial clearance compared with WT mice, which was accompanied by enhanced lung inflammation. CLP did not influence the responsiveness of alveolar macrophages toward P. aeruginosa ex vivo irrespective of the st2 genotype. In contrast, CLP resulted in a reduced capacity of WT CD4(+) and CD8(+) T cells to produce IFN-γ and tumor necrosis factor-α, an immune suppressive effect that was not seen in ST2KO mice.


CONCLUSIONS
These findings indicate that gene products of ST2 contribute to the immune-compromised state during sepsis and the ensuing disturbed homeostasis of lung host defense.
University of Amsterdam, Amsterdam, The Netherlands. j.j.hoogerwerf@amc.uva.nl
Jacobien J
JJ
Hoogerwerf
Masja
M
Leendertse
Catharina W
CW
Wieland
Alex F
AF
de Vos
J Daan
JD
de Boer
Sandrine
S
Florquin
Tom
T
van der Poll
D000818:Animals; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D007113:Immunity, Innate / Q000502:physiology; D000072179:Interleukin-1 Receptor-Like 1 Protein; D053208:Kaplan-Meier Estimate; D016676:Macrophages, Alveolar / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018410:Pneumonia, Bacterial / Q000235:genetics* / Q000276:immunology* / Q000401:mortality; D011552:Pseudomonas Infections / Q000235:genetics* / Q000276:immunology* / Q000401:mortality; D011897:Random Allocation; D018123:Receptors, Interleukin / Q000378:metabolism*; D018805:Sepsis / Q000235:genetics* / Q000276:immunology* / Q000401:mortality; D018709:Statistics, Nonparametric; D015996:Survival Rate; D048069:Tumor Necrosis Factors / Q000378:metabolism
D016207:Cytokines; C486189:Il1rl1 protein, mouse; D000072179:Interleukin-1 Receptor-Like 1 Protein; D018123:Receptors, Interleukin; D048069:Tumor Necrosis Factors