The Role of Microbiota in Neutrophil Regulation and Adaptation in Newborns

Abstract

Newborns are highly susceptible to infections and mainly rely on innate immune functions. Reduced reactivity, delayed activation and subsequent failure to resolve inflammation however makes the neonatal immune system a very volatile line of defense. Perinatal microbiota, nutrition and different extra-uterine factors are critical elements that define long-term outcomes and shape the immune system during the neonatal period. Neutrophils are first responders and represent a vital component of the immune system in newborns. They have long been regarded as merely executive immune cells, however this notion is beginning to shift. Neutrophils are shaped by their surrounding and adaptive elements have been described. The role of “innate immune memory” and the main triangle connection microbiome—neutrophil—adaptation will be discussed in this review.

LPS Induces Opposing Memory-like Inflammatory Responses in Mouse Bone Marrow Neutrophils

“…Taken together, the induction of opposing immune reactions shaped by LPS may serve as a binary switch to either efficiently eradicate pathogens (training as a resistance mechanism), or to support the resolution of inflammation (tolerance as persistence response) [25,84]. Recent studies on trained neutrophils, which may alter the diseases state or promote anti-tumoral activities, highlight the importance of memory-like responses during pathologies [34,35].…”

“…Neutrophils are among the first responder cells of the innate immunity that enter the site of infection. They are the most abundant type of immune cells and the largest group of polymorphonuclear cells [23][24][25]. As terminally differentiated cells, neutrophils harbor an armory of antimicrobial agents, such as hydrolytic enzymes and pro-inflammatory mediators, and produce reactive oxygen species (ROS) in order to protect against a variety of different viral, bacterial, as well as fungal infections [26][27][28].…”

The Role of the Pathogen Dose and PI3Kγ in Immunometabolic Reprogramming of Microglia for Innate Immune Memory

“…Recent studies by our group revealed that microglia from neonatal brains display features of trained immunity and immune tolerance after repeated contact with pathogens in a dose-dependent manner [ 10 , 46 ]. Intriguingly, naïve microglia exhibit a remarkable sensitivity to bacterial PAMPs [ 47 ], possibly to prevent hazardous events in newborns, who are highly susceptible to infections and mainly rely on innate immunity [ 48 ]. Our findings confirmed the high susceptibility of microglia to PAMPs by showing that priming with ultralow LPS dosages induced elevated proinflammatory responses [ 10 ].…”

PI3Kγ Mediates Microglial Proliferation and Cell Viability via ROS

“…Our study uncovers the inhibition of PI3Kγ lipid kinase activity as a mechanism causing suppression of the microglial proliferation of LPS or ATP. The dose levels of the prototypical bacterial PAMP as well as the DAMP triggering robust microglial activation used in our in vitro systems were based on our previous work [10,24,29,44]. Nevertheless, it should be recognized that relevant cellular immune responses can be induced-at least in naïve microglia-with much lower LPS concentrations.…”