Contributions
Abstract: P434
Type: Poster Sessions
Abstract Category: Pathology and pathogenesis of MS - Immunology
Introduction: Regulation of neuroinflammation is necessary to maintain central nervous system (CNS) homeostasis and has therapeutic potential in diseases such as multiple sclerosis. The CNS contains parenchymal and extraparenchymal myeloid cells that can play a regulatory role. We have examined the capacity of innate-signaled myeloid cells to regulate experimental autoimmune encephalomyelitis (EAE) in mice.
Methods: Mice received a fluorescent-conjugated bispecific NOD2- and TLR9-agonist microparticle MIS416 either intravenously or by intrathecal injection to extraparenchymal leptomeningeal, ventricular and subarachnoid space. MIS416 has previously been shown to suppress EAE when given peripherally.
Results: Intravenous MIS416 induced significant extraparenchymal infiltration from blood of monocytic myeloid cells (CD45high, Ly6C+, F4/80+, CD11b+, CD11c+) that had phagocytosed MIS416. Intrathecal MIS416 induced infiltration of similar magnitude but in contrast to peripheral injection, over 30% of the MIS416-phagocytosing cells were granulocytic (Ly6Ghigh, Ly-6Clow, Gr1high, CD11b+, CD11c-). Both populations were also PDL1+. mRNA for the neutrophil-recruiting chemokines CXCL1 and CXCL2 were upregulated in CNS. When given to mice showing first symptoms of EAE, intrathecal MIS416 suppressed disease - this did not occur in mice lacking the Type I IFN receptor. Extraparenchymal MIS416-phagocytosing cells, including polymorphonuclear neutrophils, were shown to produce IFNβ in reporter mice, and sorted monocytic and granulocytic cells expressed IRF7, indicating IFN response.
Conclusions: CNS-innate signaling uniquely recruits granulocytic myeloid-derived phagocytes from blood. These and co-infiltrating phagocytic monocytic myeloid cells produce IFNβ and suppress EAE by a Type I IFN-dependent mechanism. This endogenously-triggered pathway likely contributes to CNS homeostasis and may have therapeutic potential.
Disclosure: J. Marczynska: nothing to disclose
R. M. Khorooshi: nothing to disclose
R. Storgaard Dieu: nothing to disclose
C. Rønn Hansen: nothing to disclose
S. Kavan: nothing to disclose
M. Thomassen: nothing to disclose
M. Burton: nothing to disclose
T. Kruse: nothing to disclose
G. A. Webster: employee of Innate Immunotherapeutics, which is commercialising MIS416 as an immune modulator.
T. Owens: nothing to disclose
Abstract: P434
Type: Poster Sessions
Abstract Category: Pathology and pathogenesis of MS - Immunology
Introduction: Regulation of neuroinflammation is necessary to maintain central nervous system (CNS) homeostasis and has therapeutic potential in diseases such as multiple sclerosis. The CNS contains parenchymal and extraparenchymal myeloid cells that can play a regulatory role. We have examined the capacity of innate-signaled myeloid cells to regulate experimental autoimmune encephalomyelitis (EAE) in mice.
Methods: Mice received a fluorescent-conjugated bispecific NOD2- and TLR9-agonist microparticle MIS416 either intravenously or by intrathecal injection to extraparenchymal leptomeningeal, ventricular and subarachnoid space. MIS416 has previously been shown to suppress EAE when given peripherally.
Results: Intravenous MIS416 induced significant extraparenchymal infiltration from blood of monocytic myeloid cells (CD45high, Ly6C+, F4/80+, CD11b+, CD11c+) that had phagocytosed MIS416. Intrathecal MIS416 induced infiltration of similar magnitude but in contrast to peripheral injection, over 30% of the MIS416-phagocytosing cells were granulocytic (Ly6Ghigh, Ly-6Clow, Gr1high, CD11b+, CD11c-). Both populations were also PDL1+. mRNA for the neutrophil-recruiting chemokines CXCL1 and CXCL2 were upregulated in CNS. When given to mice showing first symptoms of EAE, intrathecal MIS416 suppressed disease - this did not occur in mice lacking the Type I IFN receptor. Extraparenchymal MIS416-phagocytosing cells, including polymorphonuclear neutrophils, were shown to produce IFNβ in reporter mice, and sorted monocytic and granulocytic cells expressed IRF7, indicating IFN response.
Conclusions: CNS-innate signaling uniquely recruits granulocytic myeloid-derived phagocytes from blood. These and co-infiltrating phagocytic monocytic myeloid cells produce IFNβ and suppress EAE by a Type I IFN-dependent mechanism. This endogenously-triggered pathway likely contributes to CNS homeostasis and may have therapeutic potential.
Disclosure: J. Marczynska: nothing to disclose
R. M. Khorooshi: nothing to disclose
R. Storgaard Dieu: nothing to disclose
C. Rønn Hansen: nothing to disclose
S. Kavan: nothing to disclose
M. Thomassen: nothing to disclose
M. Burton: nothing to disclose
T. Kruse: nothing to disclose
G. A. Webster: employee of Innate Immunotherapeutics, which is commercialising MIS416 as an immune modulator.
T. Owens: nothing to disclose