Long-term immune dysfunction induced by sepsis is dependent on age

Background and Purpose: Sepsis survival in adults is commonly followed by immunosuppression and increased susceptibility to secondary infections. Nonetheless, the long-term immune consequences of pediatric sepsis are unknown. 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 IL-33/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.