Inflammation induced by innate immunity influences the development of T cell–mediated autoimmunity in multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE). We found that strong activation of innate immunity induced Nod-like receptor protein 3 (NLRP3) inflammasome–independent and interferon-β (IFNβ)-resistant EAE (termed type B EAE), whereas EAE induced by weak activation of innate immunity requires the NLRP3 inflammasome and is sensitive to IFNβ treatment. Instead, an alternative inflammatory mechanism, including membrane-bound lymphotoxin-β receptor (LTβR) and CXC chemokine receptor 2 (CXCR2), is involved in type B EAE development, and type B EAE is ameliorated by antagonizing these receptors. Relative expression of Ltbr and Cxcr2 genes was indeed enhanced in patients with IFNβ-resistant multiple sclerosis. Remission was minimal in type B EAE due to neuronal damages induced by semaphorin 6B upregulation on CD4+ T cells. Our data reveal a new inflammatory mechanism by which an IFNβ-resistant EAE subtype develops.
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We thank A. Uezu for help in primary hippocampal neuron culture and Golgi staining, S. McKinnon for help in isolating optic nerves, M. Luftig for MHV68 experiments and M. Skeen for discussions on IFNβ treatment of MS patients. We are also grateful to S. Cote, S. Arvai, and all participants in the MURDOCK Study Community Registry and Biorepository and the MURDOCK Multiple Sclerosis Cohort Study. We thank MURDOCK Study leadership and staff, including principal investigator K. Newby, for providing samples and support. This study was funded by the National Multiple Sclerosis Society (RG4536 to M.L.S.; RG4723 to C.L.) and NIH (R01MH096979 and P41EB015897 to C.L.).
The authors declare no competing financial interests.
Integrated supplementary information
Supplementary Figure 1 EAE induced by several immunization methods and phenotypic effects on cell migration, demyelination and nociceptive sensitivity in mice with type A and type B EAE.
(a) EAE severity in Nlrp3-/- mice was evaluated. EAE was induced with 6 different methods, as indicated in Online Methods. (b) AUC between 0 and 20-dpi. Method 1 (n=4), Method 2-6 (n=5). P(Method 1 vs 2)=0.0006, t(7)=5.98, P(Method 1 vs 3) <0.0001, t(7)=12.54, P(Method 1 vs 4)=0.0027, t(7)=4.54, P(Method 1 vs 5) <0.0001, t(7)=8.15, P(Method 1 vs 6) <0.0001, t(7)=10.63. (c) Numbers of total immune cells were evaluated in the brains and spinal cords (S.C.) of mice with Type-B EAE at 17-dpi. n=4. Brain: P(WT vs Nlrp3-/-)=0.8159, t(6)=0.2433, P(WT vs Asc-/-)=0.5685, t(6)=0.6031. Spinal cord: P(WT vs Nlrp3-/-)=0.5226, t(6)=0.6787, P(WT vs Asc-/-)=0.8984, t(6)=0.1332. (d) IFNβ treatment on Nlrp3-/- mice with Type-B EAE induced with Method 6. IFNβ (3x104 unit/mouse) were i.p. injected every other day from day 0 to 8 as previously performed. (e) Time course on body weight change in Type-A and Type-B EAE. (f) Il1b mRNA levels in splenic DC from naïve, Type-A, and Type-B EAE mice at 9 dpi. P(Naive vs Type-A)=0.0059, t(4)=5.344, P(Naive vs Type-B)<0.0001, t(4)=18.55, P(Type-A vs Type-B)=0.0004, t(4)=10.83. (g,h) Levels of extracellular IL-1β (f) and p20 caspase-1 (g) in 24h splenocyte culture supernatants (n=4 for Type-A, n=5 for Type-B). P=0.0261, t(6)=2.724 (g). P=0.0020, t(6)=4.794 (h). (i) Infiltrated cell numbers in the brain and spinal cord (n=7). Brain: P(Total)=0.0028, t(12)=3.747, P(CD4)=0.018, t(12)=2.737, P(Th17)=0.0167, t(12)=2.78, P(Th1)=0.0165, t(12)=2.784, P(CD8)=0.0329, t(12)=2.41, P(B)=0.0013, t(12)=4.165, P(DC)=0.0003, t(12)=5.008, P(PMN)=0.0004, t(12)=4.912, P(Mac)=0.0027, t(12)=3.759. Spinal cord: P(Total)=0.0035, t(12)=3.621, P(CD4)=0.0002, t(12)=5.372, P(Th17)=0.0003, t(12)=4.997, P(Th1)=0.00465, t(12)=2.221, P(CD8)=0.0104, t(12)=3.032, P(B)=0.0918, t(12)=1.833, P(DC)=0.0429, t(12)=2.263, P(PMN)=0.0011, t(12)=4.29, P(Mac)=0.089, t(12)=1.849. (j) Representative LFB-stained images of brains at 17-dpi. Red arrows indicate reduced LFB intensity, i.e., reduced myelin. Scale bars, 200 μm. (k) T2 FLAIR MRI analysis of spinal cords obtained from mice at 18-dpi. Yellow arrows indicate areas of potential myelin loss. (l) Thermal sensitivity evaluated by a hot-plate test in 9-dpi mice, which did not show any EAE symptoms and motor dysfunction. n=8. P(Naive vs Type-A)=0.1524, t(14)=1.514, P(Naive vs Type-B)=0.0013, t(14)=4.026, P(Type-A vs Type-B)=0.0217, t(14)=2.582. *; p<0.05. All statistical analyses in this figure were performed by two-tailed unpaired Student’s t-test. All the experimental data and images are representatives from at least 2 similar experiments for each.
(a) Flow charts showing mLT expression in DC (CD11c+ gated) obtained from naïve mice, Type-A EAE mice, and Type-B EAE mice at 9-dpi. (b) Percentages of LTα+ (i.e., mLT+) macrophages, determined by flow cytometry, in DLNs of naïve mice or mice with EAE at 9-dpi. Naïve (n=4), Type-A (n=3), Type-B (n=4). P(Naive vs Type-A)=0.1340, t(5)=1.7887, P(Naive vs Type-B)=0.0024, t(6)=45.021, P(Type-A vs Type-B)=0.0268, t(5)=3.101, by two-tailed unpaired Student’s t-test. (c) Evaluating mLT expression on DCs from mice received CFA injection alone without MOG. One group received 200 μg Mtb in CFA (Mtb dosage for Type-A EAE), and another group had 400 μg Mtb in CFA twice (Mtb dosage for Type-B EAE). (n=6) P(Naive vs Type-A)=00.7939, t(6)=0.2732, P(Naive vs Type-B)=0.0040, t(6)=4.519, P(Type-A vs Type-B)=0.0095, t(6)=3.748, by two-tailed unpaired Student’s t-test. (d) Methylation analysis was carried out by bisulfite conversion on the Lta promoter in DCs from naïve mice. Methylated and unmethylated CpG were shown with black and gray boxes, respectively
Heatmap for differentially expressed genes in CD4+ T cells isolated from naïve, Type-A EAE mice, and Type-B EAE mice at 9-dpi. Genes and samples have been clustered using correlation distance with complete linkage. A gene is listed on the heatmap if it had a p-value <= 0.05 and a log2FC >1 or < -1.
Supplementary Figure 4 Comparison of cell populations and gene expression in mice and RRMS patients who have diseases that do not respond to IFNβ therapies.
(a) Numbers of indicated cell types obtained from DLNs and spleen on 17-dpi were evaluated between Type-A and Type-B EAE. n=4. DLNs: P(Total)=0.2073, t(6)=1.413, P(CD3)=0.8466, t(6)=0.202, P(CD4)=0.9285, t(6)=0.09353, P(CD8)=0.7413, t(6)=0.3459, P(B)=0.4141, t(6)=0.8773, P(Th17)=0.9724, t(6)=0.03605, P(Th1)=0.9017, t(6)=0.1289, P(Treg)=0.3556, t(6)=1.001. Spleen: P(Total)=0.0072, t(6)=3.99, P(CD3)=0.2537, t(6)=1.262, P(CD4)=0.1781, t(6)=1.525, P(CD8)=0.3999, t(6)=0.906, P(B)=0.1371, t(6)=1.715. (b, c) Representative flow charts (b) and proportion (c) for GM-CSF-producing Th1 and Th17 cells from Type-A and Type-B EAE at 9-dpi. n=6. Th17: P=0.6568, t(10)=0.4579, Th1: P=0.3954, t(10)=0.8879. (d) Proportion for IFNγ-, GM-CSF-, IL-22-producing and CD5L-expressing Th17 cells in spinal cords from Type-A and Type-B EAE mice at 17-dpi. Type-A (n=4), Type-B (n=5). P(IFNγ)=0.3493, t(7)=1.0037, P(GM-CSF)=0.1760, t(7)=1.505, P(Il-22)=0.2859, t(7)=1.155, P(CD5L)=0.2641, t(7)=1.214. (e) Proportions and MFI of CXCR2+ neutrophils and macrophages obtained from naïve mice and mice with either Type-A or Type-B EAE at 9-dpi. n=4. PMN %: P(Naive vs Type-A)=0.0102, t(6)=3.695, P(Naive vs Type-B)=0.0004, t(6)= 7.001, P(Type-A vs Type-B)=0.0022, t(6)=5.131. PMN MFI: P(Naive vs Type-A)=0.0777, t(6)=2.125, P(Naive vs Type-B)=0.0014, t(6)= 5.588, P(Type-A vs Type-B)=0.0090, t(6)=3.81. Macrophage %: P(Naive vs Type-A)=0.0005, t(6)=6.774, P(Naive vs Type-B)=0.0006, t(6)= 6.48, P(Type-A vs Type-B)=0.0161, t(6)=3.314. Macrophage MFI: P(Naive vs Type-A)=0.33, t(6)=1.06, P(Naive vs Type-B)=0.0001, t(6)= 11.11, P(Type-A vs Type-B)=0.0001, t(6)=10.89. (f) Flow cytometry results showing CXCR2 protein expression on the CD4+ T surface in each group (naïve mice, Type-A, or Type-B EAE mice at 9-dpi). (g) Comparison of relative gene expression levels between LTBR and CXCR1, CXCR1 and CXCR2, LTBR and CXCR2, normalized to VCAM1 expression. Total PBMCs from RRMS patients who responded to IFNβ and those who did not respond to IFNβ were compared. All statistical analyses in this figure were performed by two-tailed unpaired Student’s t-test. All the experimental data sets, except for (g), are representatives from at least 2 similar experiments for each.
Shown are representative images of typical CXCL1 staining in spinal cords from naïve mice and mice with either Type-A or Type-B EAE at 9-dpi. Scale bars, 200 μm. Images are representatives from 3 similar experiments.
(a-e) Shown are representative images of typical staining from multiple mice. (a) H/E staining in the spinal cord of Type-A and Type-B EAE mice at 70-dpi. (b) IGF-1 staining in spinal cord of naïve mice and mice with either Type-A or Type-B EAE at 22-dpi. (c) Bielschowsky neuron staining in spinal cords of naïve mice (e), and Type-A and Type-B EAE at 30-dpi. Red arrows indicate area showing reduced staining intensity in the spinal cord. (d,e) Golgi’s silver staining in spinal cord of naïve mice (d), and Type-A and Type-B at 22-dpi (e). All scale bars in this figure except magnified figure in (e), 200 μm. All scale bars in magnified figure in (e), 50 μm. All images are representatives from 3 similar experiments.
Sema6b expression levels in CD4+ T cells isolated from naïve or Type-B EAE mice at 9-dpi were evaluated by qPCR. Sema6b was knocked down by shRNA in the indicated group of CD4+ T cells. Control shRNA (scrambled shRNA sequence) was used for the control group. Values shown are obtained from three independent trials using one mouse per each. n=3. P(Naive T vs Type-B T+Control shRNA)=0.0011, t(4)=8.396, P(Type-B T+Control shRNA vs Type-B T+Sema6b shRNA)=0.0051, t(4)=5.559. *; p<0.05.
Type-A EAE is NLRP3 inflammasome-dependent and IFNβ-sensitive. Type-B EAE is induced by immunization with higher doses of Mtb than Type-A EAE induction, and is NLRP3 inflammasome-independent and IFNβ-resistant. Type-B EAE can also be induced with Type-A EAE induction methods with MHV68 infection or with rLT (rLTα2β1) injection. In Type-B EAE, Lta gene expression is epigenetically induced in DCs and the expression of membrane-bound LT (mLT) on DCs are enhanced. mLT stimulate LTβR on CD4+ T cells, resulting in the upregulation of CXCR2 on CD4+ T cells. Blockade of LTβR (with LTβR-Fc) and CXCR2 (with SB225002) selectively inhibits the Type-B EAE progression. mLT is also involved in the induction of Sema6B in T cells. Sema6B causes neural damages, and this may be a reason for the prolonged and minimal remission in Type-B EAE.
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This video shows a mouse with Type A EAE around the peak time. (MOV 31931 kb)
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Inoue, M., Chen, Ph., Siecinski, S. et al. An interferon-β-resistant and NLRP3 inflammasome–independent subtype of EAE with neuronal damage. Nat Neurosci 19, 1599–1609 (2016). https://doi.org/10.1038/nn.4421
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