The intracellular sensor NLRP3 mediates key innate and healing responses to influenza A virus via the regulation of caspase-1.
Virus-induced interlukin-1beta (IL-1beta) and IL-18 production in macrophages are mediated via caspase-1 pathway. Multiple microbial components, including viral RNA, are thought to trigger assembly of the cryopyrin inflammasome resulting in caspase-1 activation. Here, we demonstrated that Nlrp3(-/-) and Casp1(-/-) mice were more susceptible than wild-type mice after infection with a pathogenic influenza A virus. This enhanced morbidity correlated with decreased neutrophil and monocyte recruitment and reduced cytokine and chemokine production. Despite the effect on innate immunity, cryopyrin-deficiency was not associated with any obvious defect in virus control or on the later emergence of the adaptive response. Early epithelial necrosis was, however, more severe in the infected mutants, with extensive collagen deposition leading to later respiratory compromise. These findings reveal a function of the cryopyrin inflammasome in healing responses. Thus, cryopyrin and caspase-1 are central to both innate immunity and to moderating lung pathology in influenza pneumonia.
Thomas
Paul G
PG
Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Dash
Pradyot
P
Aldridge
Jerry R
JR
Ellebedy
Ali H
AH
Reynolds
Cory
C
Funk
Amy J
AJ
Martin
William J
WJ
Lamkanfi
Mohamed
M
Webby
Richard J
RJ
Boyd
Kelli L
KL
Doherty
Peter C
PC
Kanneganti
Thirumala-Devi
TD
D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D020170:Caspase 1 / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D007113:Immunity, Innate; D009980:Influenza A virus / Q000276:immunology*; D053583:Interleukin-1beta / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein
D002352:Carrier Proteins; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D020170:Caspase 1