Essential Role of Indoleamine 2, 3‐dioxygenase 1 (IDO1) in Metabolic Programming of Innate Immune Responses in Aged Lung during Influenza

Abstract

RationaleInfluenza epidemics remain a leading cause of morbidity and mortality worldwide, with highest incidence of hospitalization and death occurring in persons >65 years of age. Due to increased prevalence of comorbidities in older persons and impaired immune responses to vaccination there is a pressing need to understand the molecular mechanisms that underlie these impairments and develop cutting‐edge therapies that specifically target and amplify innate immune responses in older persons. Using our clinical findings as a foundation, the goal of this study was to interrogate biochemical profiles manifested in mouse lung tissue originating from young adult and aged adult mice over a seven‐day course of infection, with the aim of characterizing metabolic migration in lung during influenza.MethodsIn vivoYoung adult (2 months of age) and aged adult (18 months of age) BALB/c mice were intranasally instilled with 3.5 × 103 PFU of influenza (A/PR/8/1934 H1N1) (PR8). Lung tissue and bronchoalveolar lavage samples were collected at select time points during infection. Cellularity, viral titers, cytokine production, and metabolite composition were assessed.In vitroBone marrow derived and alveolar macrophages from young adult and aged adult mice were used to examine the in vitro role of cellular metabolites in mediating pro‐inflammatory cytokine production in response to TLR stimulation. Real time PCR, ELISA, and western blotting were used to examine changes in gene and protein expression, respectively.Measurements and Main ResultsDuring the course of influenza, there was heightened inflammation, cellular infiltration, edema, and alveolitis present in the aged lung that corresponded with increased viral titers, morbidity, and mortality. Focusing on the biochemical and pathway changes illustrated an important role for kynurenine and tryptophan metabolism in modulating lung specific immune responses to influenza. There was a significant decrease in kynurenine production in aged alveolar macrophages by day 7 post influenza infection that was associated with increased inflammatory and diminished regulatory responses. Despite a rapid increase in indoleamine 2,3‐dioxygenase (IDO1) expression in young, there was impaired expression and activity in aged macrophages and lung during the course of infection. Further, treatment with a mitochondrial targeted antioxidant improved IDO1 activity, rescued kynurenine production, and decreased inflammation in aged lung during influenza infection.ConclusionsIn response to influenza, age‐associated mitochondrial dysfunction contributed to changes in IDO1 expression and decreased kynurenine production in aged lung and alveolar macrophages, which resulted in heightened and sustained pro‐inflammatory responses. Treatment with a mitochondrial targeted antioxidant improved IDO1 mediated production of kynurenine as well as ameliorated morbidity and mortality in aged mice. Taken together, our data provide additional evidence as to why older persons are more susceptible to influenza and suggest a possible therapeutic to improve immunometabolic responses in this population.Support or Funding InformationR01AG052530 (H.W.S), R01AG056699 (H.W.S), K08HL138285 (S.J.C)