Temporal expression of cytokines and STAT3 activation after neonatal hypoxia/ischemia in mice

SHRIVASTAVA KALPANA; LLOVERA GEMMA; RECASENS MIREIA; CHERTOFF MARIELA; GIMINEZ LLORT LYDIA; GONZALEZ BERTA; ACARIN LAIA

DEVELOPMENTAL NEUROSCIENCE

KARGER

Lugar: Basel; Año: 2013 p. 1 - 14

0378-5866

Hypoxia/ischemia (HI) is a prevalent reason for neonatal brain injury with inflammation being an inevitable phenomenon following such injury; but there is a scarcity of dataregarding the signaling pathway involved and the effector molecules. The signal transducer and activator of transcription factor 3 (STAT3) is known to modulate injury followingimbalance between pro- and anti-inflammatory cytokines in peripheral and central nervous system injury making it a potential molecule for study. The current study investigatesthe temporal expression of interleukin (IL)-6, IL-1beta, tumor necrosis factor-alpha, IL-1ra, IL-4, IL-10, IL-13 and phosphorylated STAT3 (pSTAT3) after carotid occlusion and hypoxia (8% O2 , 55 min) in postnatal day 7 C57BL/6 mice from 3 h to 21 days after hypoxia. Protein array illustrated notable changes in cytokines expressed in both hemispheres in a time-dependent manner. The major pro-inflammatory cytokines showing immediate changes between ipsi- and contralateral hemispheres were IL-6 and IL-1beta. The anti-inflammatorycytokines IL-4 and IL-13 demonstrated a delayed augmentation with no prominent differences between hemispheres, while IL-1ra showed two distinct peaks of expressionspread over time. We also illustrate for the first time the spatiotemporal activation of pSTAT3 (Y705 phosphorylation) after a neonatal HI in mice brain. The main regions expressing pSTAT3 were the hippocampus and the corpus callosum.pSTAT3+ cells were mostly a subpopulation of activated astrocytes (GFAP+) and microglia/macrophages (F4/80+) seen only in the ipsilateral hemisphere at most time pointsstudied (till 7 days after hypoxia). The highest expression of pSTAT3+ cells was observed to be around 24 - 48 h, where the presence of pSTAT3+ astrocytes and pSTAT3+ microglia/macrophages was seen by confocal micrographs. In conclusion, our study highlights a synchronized expression of some pro- and anti-inflammatory cytokines, especially inthe long term not previously defined. It also points towards a significant role of STAT3 signaling following micro- and astrogliosis in the pathophysiology of neonatal HI-relatedbrain injury. In the study, a shift from pro-inflammatory to anti-inflammatory cytokine profile was also noted as the injury progressed. We suggest that while designing efficientneuroprotective therapies using inflammatory molecules, the time of intervention and balance between the pro- and anti-inflammatory cytokines must be considered.