CD93 regulates central nervous system inflammation in two mouse models of autoimmune encephalomyelitis.

Microglia and non-professional immune cells (endothelial cells, neurons) participate in the recognition and removal of pathogens and tissue debris in the injured central nervous system through major pro-inflammatory processes. However, the mechanisms involved in regulating these responses remain ill-characterized. We herein show that CD93, also known as complement C1qRp/AA4 stem cell marker, has an important role in the regulation of inflammatory processes. The role of CD93 was evaluated in two models of neuroinflammation. We used the MOG-experimental autoimmune encephalomyelitis (EAE) model and the antibody-dependent EAE (ADEAE), which were induced in wild-type and CD93 knockout mice. We found that CD93 was highly expressed by neurons, endothelial cells and microglia (ramified >> amoeboid). Astrocytes and oligodendrocytes did not to express CD93. We further observed that CD93-deficient (CD93-/- ) mice presented a more robust brain and spinal cord inflammation in EAE and ADEAE. Encephalitis in CD93-/- was characterized by increased numbers of infiltrating M1 macrophages (CD11c+ CD206- ) and amoeboid microglia exhibiting a more activated phenotype (Tomato Lectinhigh Cox2high ). Damage to and leakage through the blood-brain barrier was increased in CD93-/- animals and was associated with a more robust neuronal injury when compared with wild-type EAE mice. We propose that CD93 is an important neuro-immune regulator to control central nervous system inflammation.

Complement factor H, a marker of self protects against experimental autoimmune encephalomyelitis.

The CNS innate immune response is a "double-edged sword" representing a fine balance between protective antipathogen responses and detrimental neurocytotoxic effects. Hence, it is important to identify the key regulatory mechanisms involved in the control of CNS innate immunity and which could be harnessed to explore novel therapeutic avenues. In analogy to the newly described neuroimmune regulatory proteins also known as "don't eat me" signals (CD200, CD47, CD22, fractalkine, semaphorins), we herein identify the key role of complement regulator factor H (fH) in controlling neuroinflammation initiated in an acute mouse model of Ab-dependent experimental autoimmune encephalomyelitis. Mouse fH was found to be abundantly expressed by primary cultured neurons and neuronal cell lines (N1E115 and Neuro2a) at a level comparable to BV2 microglia and CLTT astrocytes. Mouse neurons expressed other complement regulators crry and low levels of CD55. In the brain, the expression of fH was localized to neuronal bodies and axons, endothelial cells, microglia but not oligodendrocytes and myelin sheaths and was dramatically reduced in inflammatory experimental autoimmune encephalomyelitis settings. When exogenous human fH was administered to disease Ab-dependent experimental autoimmune encephalomyelitis animals, there was a significant decrease in clinical score, inflammation, and demyelination, as compared with PBS-injected animals. We found that the accumulation of human fH in the brain parenchyma protected neurons from complement opsonization, axonal injury, and leukocyte infiltration. Our data argue for a key regulatory activity of fH in neuroprotection and provide novel therapeutic avenues for CNS chronic inflammatory diseases.

The multiple roles of the innate immune system in the regulation of apoptosis and inflammation in the brain.

Central nervous system (CNS) tissues contain cells (i.e. glia and neurons) that have innate immune functions. These cells express a range of receptors that are capable of detecting and clearing apoptotic cells and regulating inflammatory responses. Phagocytosis of apoptotic cells is a nonphlogistic (i.e. noninflammatory) process that provides immune regulation through anti-inflammatory cytokines andregulatory T cells. Neurons and glia express cellular death signals, including CD95Fas/CD95L, FasL, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and tumor necrosis factor receptor 1 (TNFR), through which they can trigger apoptosis in T cells and other infiltrating cells. Microglia, astrocytes, ependymal cells, and neurons express defense collagens and scavenger and phagocytic receptors that recognize apoptotic cells displaying apoptotic cell-associated molecular patterns, which serve as markers of "altered self." Glia also express pentraxins and complement proteins (C1q, C3b, and iC3b) that opsonize apoptotic cells, making them targets for the phagocytic receptors CR3 and CR4. Immunoregulatory molecules such as the complement regulator CD46 are lost from apoptotic cells and stimulate phagocytosis, whereas the expression of CD47 and CD200 is upregulated during apoptosis; this inhibits proinflammatory microglial cytokine expression, thereby reducing the severity of inflammation. This review outlines the cellular pathways used for the detection and phagocytosis of apoptotic cells in vitro and in experimental models of CNS inflammation.

C3d binding to the myelin oligodendrocyte glycoprotein results in an exacerbated experimental autoimmune encephalomyelitis.

The complement system is known to contribute to demyelination in multiple sclerosis and experimental autoimmune encephalomyelitis. However, there are few data concerning the natural adjuvant effect of C3d on the humoral response when it binds to myelin Ags. This study addresses the effect of C3d binding to the myelin oligodendrocyte glycoprotein (MOG) in the induction of experimental autoimmune encephalomyelitis in C57BL/6J mice. Immunization with human MOG coupled to C3d was found to accelerate the appearance of clinical signs of the disease and to enhance its severity compared with MOG-immunized mice. This finding was correlated with an increased infiltration of leukocytes into the central nervous system accompanied by increased complement activation and associated with areas of demyelination and axonal loss. Furthermore, B cell participation in the pathogenesis of the disease was determined by their increased capacity to act as APCs and to form germinal centers. Consistent with this, the production of MOG-specific Abs was found to be enhanced following MOG/C3d immunization. These results suggest that binding of C3d to self-Ags could increase the severity of an autoimmune disease by enhancing the adaptive autoimmune response.

The differential susceptibility of specific neuronal populations: insights from Huntington's disease.

Recent successes in identifying the genes and associated proteins underlying several familial neurodegenerative conditions have not always resulted in accounts as to why the associated patterns of neuronal damage are so specific and limited. Here, with reference to Huntington's disease, we present a general scheme to show how the mutant protein could interact with associated proteins to form an aggregation product. This could lead to neuronal death by direct actions on caspases, or by raising the levels of intracellular calcium ions and reactive oxygen species above a threshold that cannot be resisted by the protection normally conferred by endogenous factors such as calcium binding proteins, free radical scavengers and trophic factors. The local distributions of vulnerability and protective factors could ultimately dictate the pattern of damage induced by the mutant gene.