The calcineurin-NFAT axis contributes to host defense during Pseudomonas aeruginosa lung infection.

5 years ago

The calcineurin-NFAT axis contributes to host defense during Pseudomonas aeruginosa lung infection.

Cheng, McCormick, Pang, MacNeil, Chen, Junkins, Lin

Infection with the opportunistic pathogen Pseudomonas aeruginosa is effectively controlled through tightly coordinated inflammation in healthy individuals. Dysregulated inflammation in cystic fibrosis greatly increases susceptibility to P. aeruginosa and lung damage. Recently, we identified regulator of calcineurin-1, a small, conserved protein that suppresses the NFAT pathway by inhibition of calcineurin and functions as a central negative regulator of multiple inflammatory transcription factors after P. aeruginosa lung infection, implying a role for the canonical NFAT pathway in P. aeruginosa infection. Calcineurin is a calcium-calmodulin-responsive phosphatase that dephosphorylates NFAT and promotes NFAT nuclear translocation and transcriptional activity. The contribution of the NFAT pathway to host defense against P. aeruginosa remains poorly characterized. In this study, we found that NFAT was rapidly and transiently activated after P. aeruginosa infection both in vitro and in vivo. Deficiency of calcineurin Aβ caused impaired activation of NFAT and decreased inflammatory cytokine production in vivo. Finally, we demonstrated that the cross-talk between the NFAT and NFкB pathways coordinately transactivate host response genes during P. aeruginosa infection. Together, these results demonstrate for the first time that NFAT is activated through calcineurin and interacts with NFкB after P. aeruginosa lung infection, and contributes to the host inflammatory response.

Publisher URL: http://doi.org/10.1189/jlb.4A0517-197R

DOI: 10.1189/jlb.4A0517-197R