Second, we established that ILC2s make IL-13 in response to viral infection in neonatal animals

Second, we established that ILC2s make IL-13 in response to viral infection in neonatal animals. findings suggest that early-life viral infection could contribute to asthma development by provoking age-dependent, IL-25-driven type 2 immune responses. and were increased with neonatal but not adult RV infection (Fig 2, and was maintained after 8 weeks of infection (Fig E2). We also found that IL-17RB gene expression was increased (Fig 2, = 3C10/group) and mRNA measured one day after treatment. *and = 3C6/group). *decreased with anti-IL-25 treatment (Fig 6, = 4C10/group). *= 4C5 in each group). *= 3C8/group, bottom). * em P /em 0.05 versus sham, ? em P /em 0.05 versus RV+IgG (unpaired t-test). Discussion In this study, we showed that infection of mice with RV induces an age-dependent type 2 immune response in the airways. Neonatal RV infection, but not adult infection, increased expression of IL-13 and IL-25. In contrast, induction PROTAC Bcl2 degrader-1 of the type 1 cytokines IFN-, IL-12 p40 and TNF- was diminished in neonates compared to adults. The increase in IL-25 production in neonatal mice was associated with long-term expansion of IL-25-responsive ILC2s in the lungs. Further, ILC2s were a significant source of IL-13 after RV infection. Finally, RV-induced mucous cell metaplasia and airways hyperresponsiveness were attenuated by anti-IL-25. Together, these studies indicate that RV induces an age-dependent asthma-like phenotype which is driven by IL-25 and ILC2s. These studies provide a mechanism by which viral infection in early-life could lead to persistent type 2 immune responses and asthma development. The immature immune system is qualitatively different from that of adult, refractory to type 1 and permissive to type 2 responses 1C9. In our experiments, RV-induced IL-25 was regulated in an age-dependent manner and required for the development of mucous metaplasia and airways hyperresponsiveness. IL-25 appeared to be produced by RV-infected epithelial cells, though uninfected cells, including submucosal cells, may also have been involved. To our knowledge, this is the first report showing a developmental difference in the IL-25 response. Considering the epigenetic modification favoring type 2 cytokine induction in T cells 2, it is possible that the regulatory region of IL-25 is also epigenetically favored transcription in neonates compared to adults. Alternatively, blunted induction of type 1 cytokine IFN- in RV-infected neonates could be permissive for IL-25 induction. In NK cell-deficient mice, RSV infection leads to an exaggerated IL-25 response which is blocked by recombinant IFN- treatment, consistent with the notion that IFN- blocks IL-25 expression 31. Finally, it is possible that neonates experienced a greater total IL-25 response based on a higher viral load 3C7 days after inoculation. However, treatment of neonatal mice with low-dose RV also induced lung IL- 25 expression, and NK cell-deficient mice with exaggerated IL-25 production and attenuated IFN- responses have similar viral loads as wild-type mice 31, suggesting the primacy of IFN regulation. The cytokine IL-33 has been associated with development of lung ILC2s and type 2 cytokine responses in mice 32. However, IL-33 was not increased with RV infection. Thymic stromal lymphopoietin (TSLP) has also been shown to expand skin ILC2s in mice 33. RV16 infection PROTAC Bcl2 degrader-1 increases TSLP expression in human airway epithelial cells 34. It is therefore conceivable that TSLP plays a role in RV-induced ILC2 expansion. We have previously shown that this IL-13 induction is required for the development of RV-induced mucous metaplasia and airways hyperresponsiveness in neonatal mice 15. Persistent induction of IL-13-driven changes in airway inflammation and function following viral infection were first reported in Sendai-infected C57BL/6J mature mice 35. Subsequently, persistent IL-13 production has been noted following neonatal infection by RSV, pneumonia virus of mice (PVM) and influenza exposure 36C38. In the case of GADD45B mature Sendai-infected mice, IL-13 was secreted by a combination of M2-polarized macrophages and invariant NKT cells 35. In the present study, the major cells persistently secreting IL-13 were lineage-negative, CD25, CD127 double-positive ILC2s. These cells expressed c-kit, Sca-1, ST2, and IL-17RB, closely resembling lung natural helper cells and dissimilar from PROTAC Bcl2 degrader-1 nuocytes, innate helper cells or type 2 multipotent progenitor cells 21C24.. Induction of ILC2s with viral infection has previously been shown following in mature mice with influenza virus 29,39. Finally, an acute increase in ILC2s was recently shown in neonatal TLR7 null mice with PROTAC Bcl2 degrader-1 a severe PVM infection 40. However, IL-13 production by ILC2s was not assessed, and virus-induced airway inflammation and airway.

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