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

Abstract

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 Lectin Cox2 ). 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.

Key Vitamin D Target Genes with Functions in the Immune System

“…Moreover, CD93 boosts the inflammatory response of monocytes by increasing LPS recognition by TLR4. CD93 may have a protective role in autoimmune encephalomyelitis via the control of the severity of inflammation, apoptosis and bystander neuronal injury [68]. NINJ1 is a transmembrane protein expressed primarily in myeloid and endothelial cells [69] but it was first described in the peripheral nervous system inducing neurite extension.…”

CD93 is a cell surface lectin receptor involved in the control of the inflammatory response stimulated by exogenous DNA

“…4). 20,30 The brain tissue damage created in these models is likely to contribute to a major release of CpG-rich DNA from, for example, mitochondria from injured cells. 5).…”

“…7 Interestingly CD93 knockout mice have been shown to have increased severity in the context of experimentally induced ischemia and encephalitis. 20,30 The brain tissue damage created in these models is likely to contribute to a major release of CpG-rich DNA from, for example, mitochondria from injured cells. We believe that the lack…”

“…17,18 Due to their negative charges, CpG ODN as well as bacterial DNA need a receptor to bind to the cell membrane, and uptake into endosomes to bind to TLR9. Of note, it has been previously shown that neurons can express CD93 during inflammatory processes such as ischemia encephalitis 20 DEC-205 also contains a CTLD which is involved in the surface binding and uptake of CpG ODN and bacterial DNA. The capacity and the mechanisms through which DEC-205-negative cell types like neurons may respond to bacterial DNA remain ill-characterized.…”

“…The capacity and the mechanisms through which DEC-205-negative cell types like neurons may respond to bacterial DNA remain ill-characterized. Of note, it has been previously shown that neurons can express CD93 during inflammatory processes such as ischemia encephalitis 20 DEC-205 also contains a CTLD which is involved in the surface binding and uptake of CpG ODN and bacterial DNA. In light of a common structure organization between DEC-205 and CD93, we hypothesized that the latter could also contribute to cell surface recognition of CpG motifs of bacterial DNA.…”