Interleukin 15 expression in the CNS: Blockade of its activity prevents glial activation after an inflammatory injury

Abstract

Although reactive glia formation after neuronal degeneration or traumatic damage is one of the hallmarks of central nervous system (CNS) injury, we have little information on the signals that direct activation of resting glia. IL-15, a pro-inflammatory cytokine involved in regulating the response of T and B cells, may be also key for the regulation of early inflammatory events in the nervous system. IL-15 was expressed in the CNS, most abundantly in cerebellum and hippocampus, mainly in astrocytes and in some projection neurons. Using a rodent model of acute inflammatory injury [lipopolysaccharide (LPS) injection], we found enhanced expression of IL-15 in both reactive astroglia and microglia, soon after CNS injury. Blockade of IL-15 activity with an antibody to the cytokine, reversed activation of both glial types, suggesting that IL-15 has a major role in the generation of gliotic tissue and in the regulation of neuroimmune responses. Because IL-15 appears to modulate the inflammatory environment acutely generated after CNS injury, regulating IL-15 expression seems a clear antiinflammatory therapy to improve the outcome of neurodegenerative diseases and CNS trauma.

Contribution of Astrocyte-Derived IL-15 to CD8 T Cell Effector Functions in Multiple Sclerosis

“…Moreover, several studies have documented the capacity of human monocytes/ macrophages for providing functional IL-15 to T cells (20,23), supporting the notion that CNS macrophages and most likely microglia do the same. In line with our findings, astrocytes have been shown to be the main source of IL-15 in LPS-injected mice, with reactive microglia being an additional source (38). Dendritic cells, found mainly in the perivascular spaces in MS lesions, could serve as an additional source of IL-15 (21).…”

“…Thus, it is essential to document functional surface IL-15 protein expression in human CNS cells. Although the IL-15 protein has been detected on astrocytes in inflammatory mouse models (36,38), whether these nonmyeloid cells represent an important and functional IL-15 source in human CNS diseases specifically for CD8 T cells has not been addressed. Astrocytes are implicated as contributors to both innate and adaptive immune responses taking place in the CNS (39).…”

Temporal dynamics of hippocampal neurogenesis in chronic neurodegeneration

“…Mice perfusion, tissue processing and immunohistochemical analysis was performed as previously described (Gomez-Nicola et al , 2008, 2014) using the following primary antibodies: rabbit anti-PCNA (Abcam), rabbit anti-phospho-Histone H3 (Cell Signaling), rabbit anti-Ki67 (Abcam), mouse anti-BrdU (DSHB), rat anti-BrdU (Santa Cruz Biotechnologies), goat anti-doublecortin (DCX; Santa Cruz Biotechnologies), guinea pig anti-doublecortin (DCX; Millipore), rabbit anti-calretinin (Millipore), goat anti-Sox2 (Santa Cruz Biotechnologies), mouse anti-NeuN (Millipore), mouse anti-synaptophysin (Millipore) and rabbit anti-cleaved caspase 3 (Millipore). After primary antibody incubation, the sections were washed and incubated with the appropriate biotinylated secondary antibody (Vector Labs), and/or with the appropriate Alexa Fluor® 405, 488 or 568 conjugated secondary antibody or streptavidin (Molecular Probes).…”

Astrocyte-derived interleukin-15 exacerbates ischemic brain injury via propagation of cellular immunity

“…Some studies have demonstrated that IL-15 contributes to the immunopathology of several inflammatory diseases, such as rheumatoid arthritis and inflammatory bowel disease (26,27). Despite recent studies suggesting astrocytes as a major source of IL-15 in the inflamed CNS (28)(29)(30), the potential role of astrocytic IL-15 in ischemic brain injury remains elusive.…”