LPS-induced CCL2 expression and macrophage influx into the murine central nervous system is polyamine-dependent |
| |
Authors: | Puntambekar Shweta S Davis Deirdre S Hawel Leo Crane Janelle Byus Craig V Carson Monica J |
| |
Institution: | a Division of Biomedical Sciences, Center for Glial-Neuronal Interactions, University of California, Riverside, CA, USA b Graduate Program in Cell, Molecular and Developmental Biology, University of California, Riverside, CA, USA c Graduate Program in Biomedical Sciences, University of California, Riverside, CA, USA |
| |
Abstract: | Increased polyamine production is observed in a variety of chronic neuroinflammatory disorders, but in vitro and in vivo studies yield conflicting data on the immunomodulatory consequences of their production. Ornithine decarboxylase (ODC) is the rate-limiting enzyme in endogenous polyamine production. To identify the role of polyamine production in CNS-intrinsic inflammatory responses, we defined CNS sites of ODC expression and the consequences of inhibiting ODC in response to intracerebral injection of LPS ± IFNγ. In situ hybridization analysis revealed that both neurons and non-neuronal cells rapidly respond to LPS ± IFNγ by increasing ODC expression. Inhibiting ODC by co-injecting DFMO decreased LPS-induced CCL2 expression and macrophage influx into the CNS, without altering LPS-induced microglial or macrophage activation. Conversely, intracerebral injection of polyamines was sufficient to trigger macrophage influx into the CNS of wild-type but not CCL2KO mice, demonstrating the dependence of macrophage influx on CNS expression of CCL2. Consistent with these data, addition of putrescine and spermine to mixed glial cultures dramatically increased CCL2 expression and to a much lesser extent, TNF expression. Addition of all three polyamines to mixed glial cultures also decreased the numbers and percentages of oligodendrocytes present. However, in vivo, inhibiting the basal levels of polyamine production was sufficient to induce expression of apolipoprotein D, a marker of oxidative stress, within white matter tracts. Considered together, our data indicate that: (1) CNS-resident cells including neurons play active roles in recruiting pro-inflammatory TREM1-positive macrophages into the CNS via polyamine-dependent induction of CCL2 expression and (2) modulating polyamine production in vivo may be a difficult strategy to limit inflammation and promote repair due to the dual homeostatic and pro-inflammatory roles played by polyamines. |
| |
Keywords: | ApoD apolipoprotein D AMPA α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate CNP 2&prime 3&prime -cyclic nucleotide 3&prime -phophodiesterase CNS central nervous system Ct comparative cycle threshold DMEM Dubecco&rsquo s modified Eagle&rsquo s medium DFMO α-di-fluoro-methyl-ornithine FBS fetal bovine serum HPRT hypoxanthine phosphoribosyl transferase IL interleukin INOS inducible nitric oxide synthase LPS lipopolysaccharide MG microglia MP macrophage NMDA d-aspartic acid" target="_blank">N-methyl-d-aspartic acid ODC ornithine decarboxylase PE phycoerythrin qPCR quantitative real-time PCR SPF specific pathogen free SSAT spermine-spermidine N1-acetyl transferase TLR toll-like receptor TNF tumor necrosis factor TREM triggering receptor expressed on myeloid cells |
本文献已被 ScienceDirect PubMed 等数据库收录! |
|