Aging Promotes Neutrophil-Induced Mortality by Augmenting IL-17 Production during Viral Infection

Abstract

Summary Morbidity and mortality associated with viral infections increase with age, although the underlying mechanisms are unclear. Here, we investigated whether aging alters inflammatory responses during systemic viral infection and whether such age-related alterations contribute to viral-induced death. We found that infection of aged mice with systemic herpes viruses led to rapid increases in serum IL-17, neutrophil activation, and mortality due to hepatocyte necrosis. In contrast, all young mice survived infection, displaying weaker IL-17 induction and neutrophil activation. During viral activation, natural killer T cells isolated from the livers of aged mice exhibited greater RORγT gene expression and IL-17 production than young cells. Importantly, IL-17 neutralization or neutrophil depletion during viral infection reduced liver damage and prevented death of aged mice. These results demonstrate that, during systemic viral infection, aging alters the host-pathogen interaction to overproduce IL-17, inducing liver injury and death.

Aging, imbalanced inflammation and viral infection

“…Our work shows that aged, but not young, mice succumb to systemic herpes viral infection due to exaggerated inflammation. 34 We documented that aged mice that were infected with either herpes simplex 2 virus (HSV-2) or with murine cytomegalovirus (mCMV) exhibited a rapid rise in the proinflammatory cytokines, IL-6, IL-17 and TNFα. These results were coupled to findings of increased liver injury and necrosis with neutrophil activation in aged mice than young counterparts.…”

A Detrimental Role for Invariant Natural Killer T Cells in the Pathogenesis of Experimental Dengue Virus Infection

“…For example, using an experimental mouse model of chronic lung disease triggered by infection with Sendai virus, Kim et al 33 demonstrated that IL-13 production by iNKT cells contributes to pulmonary disease. More recently, Stout-Delgado et al 34 demonstrated that IL-17 production by iNKT cells from aged mice infected with herpes simplex virus 2 is sufficient to promote liver damage and death. In the context of sterile inflammation, iNKT cells can have deleterious effects on local and systemic responses.…”

“…20,24 -26 For example, during infection with influenza A virus, herpes simplex virus types 1 and 2, and lymphocytic choriomeningitis virus, iNKT cells have a positive role in anti-viral immune responses and virus-associated disease, [27][28][29][30][31][32] whereas during infection with Sendai virus and herpes simplex virus type 2 (only in aged mice), iNKT cells are rather deleterious. 33,34 However, iNKT cells do not seem to participate in anti-viral immunity or control of viral replication during infection with encephalomyocarditis virus and murine cytomegalovirus. [35][36][37] The potential role of iNKT cells in experimental viral infections has also been studied using CD1d-deficient mice, which lack both iNKT cells and vNKT cells.…”

The Innate Immune System and Aging: What is the Contribution to Immunosenescence ?

“…There is still controversy around whether the TLRs response to stimulation is altered with aging in macrophages or mDCs. In the mean time they seem to retain the capacity to produce pro-inflammatory cytokines and to activate CD8+ T cells [66] as well as the induction of IL-17 which is known to recruit neutrophils [67]. Thus, an exaggerated DCs response may alter the otherwise beneficial response to viral infections in elderly through a putative exaggerated proinflammatory response [68].…”

“…There are only few reports on NKT cell functioning with aging, mostly murine studies [67,104,105]. However it can be hypothesized that the altered activation of APCs via their TLR receptors will create an unfavourable milieu for NKT activation either directly or by their cytokine secretion.…”