Abstract
BackgroundPreterm and term newborns are at high risk of brain damage as well as subsequent cerebral palsy and learning disabilities. Indeed, hypoxia-ischemia (HI), pathogen exposures, and associated intracerebral increase of pro-inflammatory cytokines have all been linked to perinatal brain damage. However, the developmental effects of potential variations of pro- and anti-inflammatory cytokine ratios remain unknown.MethodsUsing rat models of perinatal brain damage induced by exposures to lipopolysaccharide (LPS) and/or HI at distinct levels of maturity, we compared cytokine expression at stages of cerebral development equivalent to either preterm (postnatal day 1, P1) or term (P12) newborns.ResultsAt P1, expression of anti-inflammatory cytokine within the brain was either not modulated (IL-6, IL-10) or down-regulated (IL-1ra, TGF-β1) by HI, LPS or LPS+HI. In contrast, there was at P12 an up-regulation of all anti-inflammatory cytokines studied in HI or LPS+HI condition, but not after LPS exposure. Interestingly, IL-1β was the main pro-inflammatory cytokine up-regulated moderately at P1, and strongly at P12, with a weak co-expression of TNF-α observed mainly at P12. These age-dependant inflammatory reactions were also accompanied, under HI and LPS+HI conditions, at P12 only, by combined: (i) expression of chemokines CINC-1 and MCP-1, (ii) blood-brain barrier (BBB) leakage, and (iii) intracerebral recruitment of systemic immune cells such as neutrophils. In contrast, sole LPS induced IL-1β responses mainly within white matter at P1 and mainly within gray matter at P12, that were only associated with early MCP-1 (but no CINC-1) induction at both ages, without any recruitment of neutrophils and CD68+ cells.ConclusionHI and LPS+HI induce pro-inflammatory oriented immune responses in both preterm and term like brains, with a maximal inflammatory response triggered by the combination of LPS+HI. The profile of these neuroinflammatory responses presented striking variations according to age: no or down-regulated anti-inflammatory responses associated with mainly IL-1β release in preterm-like brains (P1), in sharp contrast to term-like brains (P12) presenting stronger anti-and pro-inflammatory responses, including both IL-1β and TNF-α releases, and BBB leakage. These developmental-dependant variations of neuroinflammatory response could contribute to the differential pattern of brain lesions observed across gestational ages in humans. This also highlights the necessity to take into consideration the maturation stage, of both brain and immune systems, in order to develop new anti-inflammatory neuroprotective strategies.
Highlights
Preterm and term newborns are at high risk of brain damage as well as subsequent cerebral palsy and learning disabilities
Brain from Postnatal day 1 (P1) rat pups exposed to combined LPS+HI presented a decreased expression of TGF-b1 (Figure 1D) compared to control level
Brain from P12 pups exposed to HI and LPS+HI, had up-regulated levels of all anti-inflammatory cytokines in the hemisphere ipsilateral to ischemia, as compared to control condition (Figure 1A-D); HI and LPS+HI contralateral hemisphere presenting similar levels of expression of anti-inflammatory cytokine as control
Summary
Preterm and term newborns are at high risk of brain damage as well as subsequent cerebral palsy and learning disabilities. Decreased oxygen and other blood nutrient supply to the brain, remote pathogen exposure, or both combined, and the associated neuroinflammatory responses are the most important perinatal risk factors associated with brain injury and subsequent cerebral palsy and/or learning and behavioral impairments [1,2,3]. The incidence of these forms of neonatal brain damage is inversely proportional to gestational age and higher in preterm than in term newborn [4]. Our hypothesis is that developmental differences in neuroinflammatory responses contribute to the age-specific patterns of brain injury
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