Abstract
Apoptotic neurons generated during normal brain development or secondary to pathologic insults are efficiently cleared from the central nervous system. Several soluble factors, including nucleotides, cytokines, and chemokines are released from injured neurons, signaling microglia to find and clear debris. One such chemokine that serves as a neuronal–microglial communication factor is fractalkine, with roles demonstrated in several models of adult neurological disorders. Lacking, however, are studies investigating roles for fractalkine in perinatal brain injury, an important clinical problem with no effective therapies. We used a well-characterized mouse model of ethanol-induced apoptosis to assess the role of fractalkine in neuronal–microglial signaling. Quantification of apoptotic debris in fractalkine-knockout (KO) and CX3CR1-KO mice following ethanol treatment revealed increased apoptotic bodies compared to wild type mice. Ethanol-induced injury led to release of soluble, extracellular fractalkine. The extracellular media harvested from apoptotic brains induces microglial migration in a fractalkine-dependent manner that is prevented by neutralization of fractalkine with a blocking antibody or by deficiency in the receptor, CX3CR1. This suggests fractalkine acts as a “find-me” signal, recruiting microglial processes toward apoptotic cells to promote their clearance. Next, we aimed to determine whether there are downstream alterations in cytokine gene expression due to fractalkine signaling. We examined mRNA expression in fractalkine-KO and CX3CR1-KO mice after alcohol-induced apoptosis and found differences in cytokine production in the brains of these KOs by 6 h after ethanol treatment. Collectively, this suggests that fractalkine acts as a “find me” signal released by apoptotic neurons, and subsequently plays a critical role in modulating both clearance and inflammatory cytokine gene expression after ethanol-induced apoptosis.
Highlights
Clearance of apoptotic neurons is critical for normal central nervous system (CNS) development and for resolution of injury due to pathologic processes
We quantified the amount of apoptotic debris 6 h after injury in fractalkine-KO mice, and found that they had increased apoptotic debris compared to wild type (WT) animals, and the amount of apoptotic debris was similar to the amount seen in the CX3CR1-KO animals (Figures 1B,F,H)
IN VIVO ETHANOL-INDUCED NEURONAL APOPTOSIS LEADS TO RELEASE OF SOLUBLE FRACTALKINE We observed increased apoptotic debris in mice that are deficient in fractalkine signaling, which suggests fractalkine plays an important role in the response to alcohol injury
Summary
Clearance of apoptotic neurons is critical for normal central nervous system (CNS) development and for resolution of injury due to pathologic processes. Failure to clear apoptotic neurons leads to secondary necrosis with leakage of intracellular contents that are toxic and inflammatory. Efficient clearance is thought to be critical in order to avoid an adverse immune reaction and secondary degeneration (Ravichandran and Lorenz, 2007). The precise mechanisms by which apoptotic neurons are cleared have yet to be elucidated. Most of the work on apoptotic cell clearance has been done in non-neural systems or in invertebrate animal models (Truman et al, 2008; Elliott et al, 2009; Gronski et al, 2009). Elucidation of molecular mechanisms used for clearance of apoptotic cells in the developing and adult mammalian brain is an important goal
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