Impaired NLRP3 inflammasome function in elderly mice during influenza infection is rescued by treatment with nigericin.
The NLRP3 inflammasome is activated in the lung during influenza viral infection; however, the impact of aging on inflammasome function during influenza infection has not been examined. In this study, we show that elderly mice infected with a mouse-adapted strain of influenza produced lower levels of IL-1β during in vitro and in vivo infection. Dendritic cells from elderly mice exhibited decreased expression of ASC, NLRP3, and capase-1 but increased expression of pro-IL-1β, pro-IL-18, and pro-IL-33 compared with dendritic cells from young infected mice. Treatment with nigericin during influenza infection augmented IL-1β production, increased caspase-1 activity, and decreased morbidity and mortality in elderly mice. Our study demonstrates for the first time, to our knowledge, that during influenza viral infection, elderly mice have impaired NLRP3 inflammasome activity and that treatment with nigericin rescues NLRP3 activation in elderly hosts.
Infectious Disease Program, Lovelace Respiratory Research Institute, Albuquerque, NM 87114, USA. hdelgado@lrri.org
Heather W
HW
Stout-Delgado
Sarah E
SE
Vaughan
Anushree C
AC
Shirali
Richard J
RJ
Jaramillo
Kevin S
KS
Harrod
D019264:Adoptive Transfer; D000375:Aging / Q000276:immunology* / Q000378:metabolism; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D015153:Blotting, Western; D002352:Carrier Proteins / Q000276:immunology* / Q000378:metabolism; D020170:Caspase 1 / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D058847:Inflammasomes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009550:Nigericin / Q000494:pharmacology*; D009976:Orthomyxoviridae Infections / Q000276:immunology* / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction
D000998:Antiviral Agents; D002352:Carrier Proteins; D058847:Inflammasomes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D020170:Caspase 1; D009550:Nigericin