The Unique Characteristics of Inflammatory Responses in Mouse Brain are Acquired During Postnatal Development

Abstract

The kinetics of leukocyte recruitment during acute inflammation in adult mouse brain differ from the stereotyped response occurring in non-CNS tissues; neutrophil recruitment is minimal and monocyte recruitment occurs after a 48 h delay. One aspect of the CNS microenvironment which may contribute to restricted leukocyte recruitment is the highly differentiated nature of resident CNS macrophages, the microglia. Thus we studied the inflammatory response to intracerebral injections of endotoxin in neonates in which microglia are less differentiated and resemble more closely macrophages of non-CNS tissues. Mice injected with endotoxin on the day of birth exhibited both neutrophil and monocyte recruitment to the parenchyma, but the response differed from that occurring in non-CNS tissues such as skin. Leukocyte recruitment was very slow, the mononuclear phagocyte response peaking 14 days after endotoxin injection. This sluggish inflammatory response was reminiscent of that previously described in fetal wounds. However, when endotoxin was injected into brains of 7-day-old neonates the inflammatory response resembled that seen in non-CNS tissues; i.e. prolific neutrophil recruitment and a brisk mononuclear phagocyte response. Thus the unusual inflammatory cell kinetics are a property of the mature CNS microenvironment; all signals necessary to support typical leukocyte recruitment are present in the brain by 7 days of age but the brain becomes able to restrict leukocyte immigration during subsequent postnatal development. Developmental changes in the host response to identical inflammatory challenges suggest a window during which the brain may be particularly vulnerable to inflammatory bystander damage.

The origin and differentiation of microglial cells during development

“…When they di erentiate into rami®ed microglia, they become less active and progressively acquire the behavior of adult microglia. This transformation is re¯ected by the fact that microglial cells in the adult and developing brain respond di erently to similar stimuli (Milligan et al, 1991b;Lawson and Perry, 1995). Most authors believe that microglial precursors within the CNS originate from mesodermal cells (hypothesis a) which enter the developing CNS through di erent routes.…”

What is the blood–brain barrier (not)?

“…In both cases, they are responding to dying neuronal elements which occurs as part of brain development or senescence. Another age-related phenomenon relates to acute neutrophilic infiltration of the brain parenchyma in response to variety of insults, which occurs readily in juvenile rodents but not postnatally or in adulthood [56,57] -this might explain the probable susceptibility of children to head injuries or CNS infections. …”

The impact of early life immune challenge on behavior and microglia during postnatal development

“…Most interestingly, differences in both morphology and number have been reported in postnatal rat pups with increased microglial numbers in male pups by P4 compared to female pups [38] . The brain's inflammatory response to central infection also develops in the first week of life as the microglial and leukocyte infiltration response to central administration of LPS is greatest at P7 in rat pups compared to P0, and the kinetics of the response are distinct from that observed in the adult rat [39] . Notably, we observed sex differences in microglial number in the dorsal raphe between SAL-injected male and female mice and treatment effects in male mice in response to LPS in both the PVN and DR.…”

“…Certainly, microglia are emerging as a key regulator of CNS development and in particular, evidence is building that sex differences in microglia during early postnatal life may contribute to long-term sex differences in brain function. [36][37][38] Microglia numbers are increased in the early postnatal period, compared to adolescence and adulthood, with peak numbers occurring in the second week of postnatal life with a gradual reduction in number in the following weeks [39] . The morphology of microglia in the first postnatal week in rodents is consistent with activated ameboid microglia found in the adult CNS [24,38,39] .…”

“…[36][37][38] Microglia numbers are increased in the early postnatal period, compared to adolescence and adulthood, with peak numbers occurring in the second week of postnatal life with a gradual reduction in number in the following weeks [39] . The morphology of microglia in the first postnatal week in rodents is consistent with activated ameboid microglia found in the adult CNS [24,38,39] . Most interestingly, differences in both morphology and number have been reported in postnatal rat pups with increased microglial numbers in male pups by P4 compared to female pups [38] .…”