LPS-induced CCL2 expression and macrophage influx into the murine central nervous system is polyamine-dependent

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+ 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.

Palmitate Induces an Anti-Inflammatory Response in Immortalized Microglial BV-2 and IMG Cell Lines that Decreases TNFα Levels in mHypoE-46 Hypothalamic Neurons in Co-Culture

“…1a). Further, we found a strong induction of C-C motif ligand 2 (CCL2), as has been previously described [33] (Fig. 1c).…”

“…Similar to other molecules of the C-C motif chemokine family, CCL2 attracts other immune cells of the body including monocytes to mediate inflammation at the stimulated site [42]. In microglia, CCL2 expression and secretion increased with LPS [33], as well as in response to high glucose conditions, which was accompanied by an increase in reactive oxygen species [43]. The microglia-derived CCL2 is thought to induce infiltration of monocytes into the brain through the blood-brain barrier, which then release high concentrations of neurotoxic cytokines leading to local inflammation [44, 45] and neuronal death [46].…”

Sequential activation of microglia and astrocyte cytokine expression precedes increased iba‐1 or GFAP immunoreactivity following systemic immune challenge

“…Cytokine induction by microglia, including IL-1b, TNFa, and IL-6, helps to propagate this immune derived signal within the brain and mediate physiological and behavioral responses (Dantzer, 2001;Dantzer et al, 2008). Chemokine induction by active microglia also transmits neuroinflammatory signals and may represent a mechanism by which resident microglia signal to peripheral immune cells (Carson et al, 2006;Cazareth et al, 2014;Fenn et al, 2014b;Puntambekar et al, 2011;Wohleb et al, 2013). In addition, microglial activation following immune challenge is associated with an acute phase response, which involves reduced iron bioavailability to limit pathogen growth and prevent excess CNS damage after injury (Parrow et al, 2013;Sauerbeck et al, 2013).…”

Pivotal Advance: Arginase-1-independent polyamine production stimulates the expression of IL-4-induced alternatively activated macrophage markers while inhibiting LPS-induced expression of inflammatory genes

“…Interestingly, pro-and anti-inflammatory properties of polyamines have been reported as well. For instance, LPS triggers infiltration of proinflammatory macrophages into the CNS and induces the production of proinflammatory factors in microglial cells in an ODC/polyamine-dependent manner [12,13]. In contrast, several studies documented an anti-inflammatory role of polyamines in monocytes and macrophages.…”