Macrophage memories of early-life injury drive neonatal nociceptive priming

The developing peripheral nervous and immune systems are functionally distinct from those of adults. These systems are vulnerable to early-life injury, which influences outcomes related to nociception following subsequent injury later in life (i.e., “neonatal nociceptive priming”). The underpinnings of this phenomenon are unclear, although previous work indicates that macrophages are trained by inflammation and injury. Our findings show that macrophages are both necessary and partially sufficient to drive neonatal nociceptive priming, possibly due to a long-lasting remodeling in chromatin structure. The p75 neurotrophic factor receptor is an important effector in regulating neonatal nociceptive priming through modulation of the inflammatory profile of rodent and human macrophages. This “pain memory” is long lasting in females and can be transferred to a naive host to alter sex-specific pain-related behaviors. This study reveals a mechanism by which acute, neonatal post-surgical pain drives a peripheral immune-related predisposition to persistent pain following a subsequent injury. [Display omitted] •Macrophages are trained by injury and drive neonatal nociceptive priming•Enrichment of p75NTR in macrophages alters neuroimmune signaling•Injury-encoded cellular memories may be maintained by bone marrow stem cells Dourson et al. investigate the effects of injury on peripheral macrophages and how they contribute to neonatal nociceptive priming. Macrophages are essential regulators of this phenomenon through modification of p75NTR. These results advance our understanding of the consequences of neonatal injury on pain processing across the lifespan.