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IL-33 regulates age-dependency of long-term immune dysfunction induced by sepsis

Colon, D. F.; Wanderley, C. W.; Turato, W.; Borges, V. F.; Franchin, M.; Castanheira, F. V. S.; Nascimento, D.; Prado, D.; de Lima, M. H.; Volpon, L. C.; Kavaguti, S. K.; Ramalho, F.; Carlotti, A. P.; Carmona, F.; Franklin, B. S.; Alves-Filho, J. C.; Cunha, F. d. Q.

2022-01-16 immunology
10.1101/2022.01.15.476447 bioRxiv
Show abstract

Sepsis survival in adults is commonly followed by immunosuppression and increased susceptibility to secondary infections. However, the long-term immune consequences of pediatric sepsis are unknown. 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. In contrast to adults, infant 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 post-septic adults but not infant mice. Impaired IL-33 production in post-septic infant mice was associated with increased DNA-methylation on lung epithelial cells. Notably, IL-33 treatment boosted the expansion of Tregs and induced immunosuppression in infant mice. Clinically, adults but not pediatric post-septic patients exhibited higher counts of Tregs and sera IL-33 levels. Hence, we describe a crucial and age-dependent role for IL-33 in post-sepsis immunosuppression.

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