Developmental regulation of the neuroinflammatory responses to LPS and/or hypoxia-ischemia between preterm and term neonates: An experimental study

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.

Postnatal administration of IL-1Ra exerts neuroprotective effects following perinatal inflammation and/or hypoxic-ischemic injuries

“…This is in agreement with other reports, which showed the neurotoxic consequence of IL-1 (Cai et al, 2004;Crampton et al, 2011;Favrais et al, 2011;Girard et al, 2008;Green et al, 2012), and also with reports on the neuroprotective potential of IL-1Ra administration seen in experimental models of neonatal brain injury induced by pure HI in rodents at a later stage of development, equivalent to term human newborns (Hagberg et al, 1996;Martin et al, 1994). Thus, even if the mechanisms leading to brain damage are known to differ across developmental stages (Anthony et al, 1997;Brochu et al, 2011), IL-1Ra appears to exert its beneficial effects when administered in models of LPS and/or HI induced brain insults, occurring (at least for HI) either in the early preterm or term brain. The beneficial effect of IL-1Ra administration could be even more important at this early developmental stage since recent work by Favrais et al showed that systemic administration of IL-1β at a specific early developmental stage (i.e.…”

“…Both LPS and HI-induced brain injuries have been associated with increased expression of pro-inflammatory cytokines (Bell and Hallenbeck, 2002;Bona et al, 1999;Brochu et al, 2011;Girard et al, 2008;Hagberg et al, 1996;Hedtjärn et al, 2004;Szaflarski et al, 1995;Urakubo et al, 2001;van den Tweel et al, 2006). Our study clearly showed that the deleterious effects of perinatal stressors could be blocked before inducing irreversible impairments.…”

“…However, there is a clear effect of postnatal administration of human IL-1Ra on damage caused by prenatal LPS. It is also possible that the protective effect of IL-1Ra on gliosis is secondary to reduced neuronal injury, although this is unlikely since, in this particular model, there is no widespread neuronal loss as compared to injury occurring at a later developmental stage or in mature animal (Girard et al, 2009;Brochu et al, 2011;McColl et al, 2007). Although endogenous levels of IL-1Ra have been associated with increased risk of post-stroke infection in humans (Tanzi et al, 2011), another study showed that exogenous administration of IL-1Ra post-stroke led to the reversal of stroke-associated peripheral immune suppression (Smith et al, 2012).…”

“…LPS has been shown not to cross the placenta (Ashdown et al, 2006) and the preconditioning effect was showed to be specific to LPS (Davis et al, 2005) and dependent on TNF (Rosenzweig et al, 2007) but not IL-1. Furthermore, the immune response is well known to differ depending on the developmental stage (Brochu et al, 2011;Anthony et al, 1997) and further studies would be necessary in order to determined if a preconditioning effect can be mediated by prenatal inflammatory events.…”

Nanomedicine in cerebral palsy

“…105 This may be dictated by ongoing inflammation in the brain, as evidenced by preclinical studies and postmortem studies in humans with periventricular leukomalacia that shows persistent, diffuse astro-and microgliosis along the periventricular region of the brain. 106,107 Positron emission and postmortem studies in traumatic brain injury have demonstrated activation of microglia in the thalamus several years after injury.…”