Premium
Nitric oxide inhibits interleukin‐1‐mediated protection against Escherichia coli K1‐induced sepsis and meningitis in a neonatal murine model
Author(s) -
Chambers Catherine A,
Lacey Carolyn A,
Brown Dana C,
Skyberg Jerod A
Publication year - 2021
Publication title -
immunology and cell biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.999
H-Index - 104
eISSN - 1440-1711
pISSN - 0818-9641
DOI - 10.1111/imcb.12445
Subject(s) - neonatal sepsis , microbiology and biotechnology , nitric oxide , biology , inflammasome , pyrin domain , escherichia coli , neonatal meningitis , nitric oxide synthase , sepsis , receptor , immunology , interleukin , pathogenesis , microglia , cytokine , inflammation , endocrinology , biochemistry , gene
Neonatal meningitis‐associated Escherichia coli (NMEC) is a leading cause of sepsis and meningitis in newborn infants. Neonates are known to have impaired inflammasome activation and interleukin (IL)‐1 production. However, it is unknown what role this plays in the context of NMEC infection. Here we investigated the role of IL‐1 signaling in the pathogenesis of NMEC infection. We found both IL‐1β and IL‐1α were secreted from macrophages and microglial cells in response to NMEC in a Toll‐like receptor 4‐ and NLR family pyrin domain containing 3 (NPLR3)‐dependent manner. Intracerebral infection of adult mice indicated a protective role of IL‐1 signaling during NMEC infection. However, IL‐1 receptor blockade in wild‐type neonatal mice did not significantly alter bacterial loads in the blood or brain, and we, therefore, investigated whether protection conferred by IL‐1 was age dependent. Neonates are known to have increased nitric oxide (NO) levels compared with adults, and we found NO inhibited the secretion of IL‐1 by macrophages in response to NMEC. In contrast to our results in wild‐type neonates, blockade of IL‐1 receptor in neonates lacking inducible nitric oxide synthase (iNOS) led to significantly increased bacterial loads in the blood and brain. These data indicate IL‐1 signaling is protective during NMEC infection in neonates only when iNOS is absent. Collectively, our findings suggest that increased NO production by neonates inhibits IL‐1 production, and that this suppresses the protective role of IL‐1 signaling in response to NMEC infection. This may indicate a general mechanism for increased susceptibility of neonates to infection and could lead to new therapeutic strategies in the future.