July 2010 Fact Sheet

Drs. Sylvie Girard and Guillaume Sébire, recently published a study in the April 2010 issue of the Journal of Immunology examining the role of maternal bacterial infection and inflammation occurring at the end of gestation. Although it is recognized as an independent risk factor for neuro-developmental disorders such as cerebral palsy, mental deficiency, and autism, it remains unclear whether the inflammation is causal or simply associated with these conditions. The two authors prepared the following literature review regarding maternal infection, inflammation and perinatal brain damage.

The mechanism linking maternal inflammation and fetal brain anomalies is still a controversial matter. In this study, we injected lipopolysaccharide (LPS, also known as endotoxin) from E. coli into the peritoneal space of gravid rats and showed that placental inflammation and the expression of pro-inflammatory cytokines, mainly IL-1beta, can be implicated in perinatal brain damage. The causal link between IL-1 and the altered brain development was documented when an IL-1 receptor antagonist, (L-1Ra) given to the gravida protected her pups (increased survival rate, decreased microglial activation, and preservation of motor functions). Perhaps, the use of IL-1Ra could be a therapeutic strategy to protect against perinatal brain damage arising from pathogen-induced gestational inflammation in humans.

Strength and limitations of the rat model?
An important strength of our animal model is the clinical relevance of the experimental design. We triggered inflammation by exposing the pups prenatally to a relatively low amount of bacterial component (LPS) at the end of the gestation, during a window of high susceptibility of the developing brain (corresponding to the level of brain development of early premature infant in humans, about 26-30 weeks of gestation). However, some limitations of our model need to be taken into account. For example, there are some obvious differences between human and rat brains (i.e. pre- vs post-natal maturation, gyrencephalic vs non-gyrencephalic architecture, amount of white matter…). It is also important to keep in mind that the inflammatory stimulus used (LPS from E. Coli) is a specific Toll-Like receptor4 agonist and therefore results cannot be generalized to other types of in utero infections that might be encountered.

Since LPS results in a broad inflammatory response, how come the IL-1Ra was so effective in minimizing placental and brain damage?
IL-1beta being the cytokine that was early and predominantly expressed within placenta exposed to LPS-induced gestational inflammation, we hypothesized that the IL-1 family might be at the apex of the inflammatory cascade of induction of other cytokines and subsequently to perinatal brain damage. Support for such a concept in human disease comes from gout in adult, and polyarthritis in children. We hypothesized that the cytokines all act together and that stopping one might disrupt the whole system. The powerful IL-1Ra protection we observed on the placenta strongly suggests that the beneficial effects on the pups were, at least in part, mediated by an indirect effect of IL-1 blockage that maintained placental integrity and its neurotrophic functions.

What if IL-1Ra were given postnatally?
Although the therapeutic potential of IL-1Ra in adult brain inflammatory model is increasingly recognized, there are to our knowledge no studies that addressed this issue in the neonatal period. Depending on the developmental time window when the IL-1Ra is administered, the impact could be beneficial without any deleterious impact on brain maturation. However, IL-1 might have physiological effects at this stage of development (e.g. likely role in myelination), so the effect of the IL-1Ra treatment should be carefully assessed both on tissue and on animal behaviour.

How do these results fit with what else has been published?
Others have published reports indicating a potential role of IL-1 in perinatal infectious/inflammatory and/or hypoxic-ischemic (HI) brain damage:

• Cai’s group showed that intra-cerebral injection of IL-1 induced brain damage (2)
• Gressens group showed that systemic IL-1 injection enhanced excitotoxic brain lesions, and the impact of maternal infection on brain development (3,4)
• Hagberg’s group showed that IL-1Ra protected against post-natal HI (5)
• Our group showed in human brain and in preclinical models, the temporal-spatial association between IL-1 expression  and neonatal brain damage (6).

This is just a short overview of the large amount of work that has been done on the role of IL-1 in perinatal brain damage. Thus, our results are in line with what has been hypothesized previously, and helps establish a causal role of IL-1 in the molecular cascade linking gestational inflammation and brain damage in the offspring. Altogether, these data suggest that post-natal IL-1 blockade might add some benefits to the prenatal blockade, not only in the initial inflammatory insult, but also in continued/sustained/prolonged inflammation.  We are currently testing this hypothesis on our preclinical models.

What is the relevancy of this to humans?
The use of IL-1Ra is less broad spectrum than, for example, glucocorticoids which are known to have some deleterious effects of brain development. Thus, a more specific treatment, aiming at one cytokine might be the key to selectively limit the negative effects of inflammation while keeping the likely role of cytokines during this important period of development. In our work, the fact that we studied the impact of IL-1Ra treatment on several end-points, including placenta integrity, cytokines expression, pups’ survival and brain development (i.e. histology and behavioural outcomes) without any short term deleterious effects is encouraging for potential translation. However, attention should be paid to the potential risk of deleterious effects of cytokine blockers, even before preclinical models are considered.

Encouragingly, there has been a recent single case report of IL-1Ra administration throughout pregnancy (as a treatment for Still disease) without any apparent deleterious impact on the fetus, birth and postnatal development so far (7). IL-1Ra is also used to treat cohorts of adults who have gout, and is also used in newborns and infants with inflammatory diseases (e.g. CAPS syndrome, CINCA/NOMID syndrome, Still disease) and seem to be efficient and well tolerated (8-10).

Citations

1. Girard S, Tremblay L, Lepage M, Sébire G. IL-1 receptor antagonist protects against placental and neurodevelopmental defects induced by maternal inflammation. J Immunol 2010;184:3997-4005.
2. Cai Z, Lin S, Pang, Rhodes PG. Brain injury induced by intracerebral injection of interleukin-1beta and tumor necrosis factor-alpha in the neonatal rat. Pediatr. Res 2004;56:377–384.
3. Plaisant F, Dommergues MA, Spedding M, Cecchelli R, Brillault J, Kato G, Muñoz C, Gressens P. Neuroprotective properties of tianeptine: interactions with cytokines. Neuropharmacology 2003;44:801-9.
4. Rousset CI, Chalon S, Cantagrel S, Bodard S, Andres C, Gressens P, Saliba E. 2006. Maternal exposure to LPS induces hypomyelination in the internal capsule and programmed cell death in the deep gray matter in newborn rats. Pediatr. Res. 59:428–433.
5. Hagberg H, Gilland E, Bona E, Hanson LA, Hahin-Zoric M, Blennow M, Holst M, McRae A, Söder O. Enhanced expression of interleukin (IL)-1 and IL-6 messenger RNA and bioactive protein after hypoxia-ischemia in neonatal rats. Pediatr Res 1996;40:603-9.
6. Girard, S., H. Kadhim, A. Larouche, M. Roy, F. Gobeil, and G. Se´bire. Pro-inflammatory disequilibrium of the IL-1 beta/IL-1ra ratio in an experimental model of perinatal brain damages induced by lipopolysaccharide and hypoxiaischemia. Cytokine 2008;43:54–62.
7. Berger CT, Recher M, Steiner U, Hauser TM. A patient’s wish: anakinra in pregnancy. Ann Rheum Dis 2009;68:1794-5.
8. Goldbach-Mansky R. Blocking interleukin-1 in rheumatic diseases. Ann N Y Acad Sci 2009;1182:111-23.
9. Neven B, Marvillet I, Terrada C, Ferster A, Boddaert N, Couloignier V, Pinto G, Pagnier A, Bodemer C, Bodaghi B, Tardieu M, Prieur AM, Quartier P. Long-term efficacy of the interleukin-1 receptor antagonist anakinra in ten patients with neonatal-onset multisystem inflammatory disease/chronic infantile neurologic, cutaneous, articular syndrome. Arthritis Rheum 2010;62:258-67.
10. Miyamae T, Inaba Y, Nishimura G, Kikuchi M, Kishi T, Hara R, Kaneko U, Shinoki T, Imagawa T, Yokokta S. Effect of anakinra on arthropathy in CINCA/NOMID syndrome. Pediatr Rheumatol Online J 2010;8:9.