Nitric oxide inhibits interleukin-1-mediated protection against Escherichia coli K1-induced sepsis and meningitis in a neonatal murine model

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.

Escherichia coli; IL-1; NLRP3; inflammasome; neonatal immunity.