Abstract
Background and Purpose: Sepsis-surviving adult individuals commonly
develop immunosuppression and increased susceptibility to secondary
infections, outcome mediated by the axis IL-33/ILC2s/M2
macrophages/Tregs. Nonetheless, the long-term immune consequences of
pediatric sepsis are indeterminate. We sought to investigate the role of
age in the genesis of immunosuppression following sepsis. Experimental
Approach: Here, we compared the frequency of Tregs, the activation of
the IL33/ILC2s axis in M2 macrophages, and the DNA methylation of
epithelial lung cells from post-septic infant and adult mice. Likewise,
sepsis-surviving mice were inoculated intranasally with Pseudomonas
aeruginosa or by subcutaneous inoculation of the B16 melanoma cell line.
Finally, blood samples from sepsis-surviving patients were collected and
the concentrations of IL-33 and Tregs frequency were assessed. Key
Results: In contrast to 6-week-old, 2-week-old mice were resistant to
secondary infection and did not show impairment in tumour controls upon
melanoma challenge. Mechanistically, increased IL-33 levels, Tregs
expansion, and activation of ILC2s and M2-macrophages were observed in
6-week-old but not 2-week-old post-septic mice. Moreover, impaired IL-33
production in 2-week-old post-septic mice was associated with increased
DNA methylation in lung epithelial cells. Notably, IL-33 treatment
boosted the expansion of Tregs and induced immunosuppression in
2-week-old mice. Clinically, adults but not pediatric post-septic
patients exhibited higher counts of Tregs and sera IL-33 levels.
Conclusion and Implications: These findings demonstrate a crucial and
age-dependent role for IL-33 in post-sepsis immunosuppression. Thus, a
better understanding of this process could lead to differential
treatments for adult and pediatric sepsis.