Abstract
There is great interest in understanding how the central nervous system (CNS) communicates with the immune system for recruitment of protective responses. Infiltrating phagocytic monocytes and granulocytes are implicated in neuroinflammation in multiple sclerosis and its animal model experimental autoimmune encephalomyelitis (EAE). To investigate how CNS endogenous signals can be harnessed to promote anti-inflammatory programs, we have used a particulate Toll-like receptor 9 and nucleotide-oligomerization domain 2 bispecific innate ligand (MIS416), to address whether its phagocytosis within the CNS recruits protective myeloid cells. We find that MIS416 injected intrathecally into the cerebrospinal fluid via the cisterna magna induced a local chemokine response that recruited blood-derived monocytes and neutrophils to the CNS. These cells phagocytosed MIS416. The increase in EAE severity normally seen from time of onset did not occur in mice receiving MIS416. This suppression of disease symptoms was dependent on expression of the type I interferon receptor (IFNAR). Transfer of intrathecal MIS416-induced neutrophils suppressed EAE in recipient mice, while monocytes did not transfer protection. MIS416-induced neutrophils showed increased IL-10 expression that was IFNAR1-driven. In contrast to intrathecal administration, intravenous administration of MIS416 led to monocyte but not neutrophil infiltration to the CNS. We thus identify a CNS-intrinsic and -specific phagocytosis-induced recruitment of anti-inflammatory neutrophils that contribute to CNS homeostasis and may have therapeutic potential.
Highlights
Interaction between the central nervous system (CNS) and the immune system exists for benefit to the host
To test whether innate immune targeting within the CNS impacts traffic of myeloid cells to the CNS, Microparticle Immune Stimulator-416 (MIS416) was administered to cerebrospinal fluid (CSF) via intrathecal injection
Blood-derived MIS416-phagocytosing cells included both monocytic myeloid cells (F4/80+GR-1low/−) and neutrophils (F4/80−Gr-1high), in similar proportions to those seen in non-chimeric mice (Fig. 1a). These findings suggested that intrathecal MIS416 induced a CNS-intrinsic inflammatory program, which led to recruitment from blood of monocytes and neutrophils into the CNS
Summary
Interaction between the central nervous system (CNS) and the immune system exists for benefit to the host. Extraparenchymal myeloid cells, that are in direct contact with cerebrospinal fluid (CSF), include perivascular and meningeal macrophages [19]. They share prenatal origin with microglia, as well as major elements of their transcriptional profile, and like microglia, these CSF cells are not normally replaced by blood-derived cells [19]. They are implicated functionally in host response to pathogens, which implies an immune recruitment capacity.
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