Figure 8: Inhibition of CD11b blocks fibrinogen-induced local T-cell activation, chemokine gene expression and peripheral inflammatory cell recruitment.

(a) Fibrinogen-induced local T-cell activation (OX-40) in the corpus callosum of WT mice is significantly reduced in Itgam^−/− mice (n=4). Representative images are shown. Data are presented as mean±s.e.m. **P<0.01, ***P<0.001 (one-way ANOVA and Bonferroni’s multiple comparisons test). Scale bar, 100 μm. (b) In vivo pharmacologic blockade of CD11b by intracerebroventricular delivery of anti-CD11b antibody reduces fibrinogen-induced Cxcl10 and Ccl2 gene expression, compared with isotype IgG control antibody. Data are presented as mean±s.e.m. (n=5 per group). *P<0.05, **P<0.01, ***P<0.001 (one-way ANOVA and Bonferroni’s multiple comparisons test). (c) Quantification of infiltrated CD3⁺ T cells and RFP⁺ macrophages in the corpus callosum 7 days after injection of fibrinogen in WT mice treated with anti-CD11b or IgG isotype control antibody. Data are presented as mean±s.e.m. (CD3, n=6–7 mice per group; RFP, n=7 mice per group). *P<0.05, **P<0.01 (non-parametric Mann–Whitney U-test). (d) Proposed model for the role of fibrin, the final product of the coagulation cascade, in the development of CNS autoimmunity. On BBB disruption, fibrinogen extravagates into the CNS and is converted to fibrin upon activation of coagulation. Fibrin, the high-affinity plasma-derived ligand for CD11b/CD18, activates CNS resident innate immune cells (microglia and perivascular macrophages) to stimulate chemokine release leading to recruitment of peripheral inflammatory macrophages/monocytes and T cells. Fibrin also induces antigen-presenting properties and provides instructive signals (such as IL-12) for inducing Th1-cell differentiation. Fibrin-induced microglial activation, recruitment of peripheral macrophages and T-cell activation lead to inflammatory demyelination. ANOVA, analysis of variance.