Neuronal ICAM-5 Inhibits Microglia Adhesion and Phagocytosis and Promotes an Anti-inflammatory Response in LPS Stimulated Microglia.

The intercellular adhesion molecule-5 (ICAM-5) regulates neurite outgrowth and synaptic maturation. ICAM-5 overexpression in the hippocampal neurons induces filopodia formation in vitro. Since microglia are known to prune supernumerous synapses during development, we characterized the regulatory effect of ICAM-5 on microglia. ICAM-5 was released as a soluble protein from N-methyl-D-aspartic acid (NMDA)-treated neurons and bound by microglia. ICAM-5 promoted down-regulation of adhesion and phagocytosis in vitro. Microglia formed large cell clusters on ICAM-5-coated surfaces whereas they adhered and spread on the related molecule ICAM-1. ICAM-5 further reduced the secretion of the proinflammatory cytokines tumor necrosis factor α (TNF-α) and interleukin 1ß (IL-1ß), but on the contrary induced the secretion of the anti-inflammatory IL-10 from lipopolysaccharide (LPS) stimulated microglia. Thus, ICAM-5 might be involved in the regulation of microglia in both health and disease, playing an important neuroprotective role when the brain is under immune challenges and as a "don't-eat-me" signal when it is solubilized from active synapses.

ICAM-5 affects spine maturation by regulation of NMDA receptor binding to α-actinin.

ICAM-5 is a negative regulator of dendritic spine maturation and facilitates the formation of filopodia. Its absence results in improved memory functions, but the mechanisms have remained poorly understood. Activation of NMDA receptors induces ICAM-5 ectodomain cleavage through a matrix metalloproteinase (MMP)-dependent pathway, which promotes spine maturation and synapse formation. Here, we report a novel, ICAM-5-dependent mechanism underlying spine maturation by regulating the dynamics and synaptic distribution of α-actinin. We found that GluN1 and ICAM-5 partially compete for the binding to α-actinin; deletion of the cytoplasmic tail of ICAM-5 or ablation of the gene resulted in increased association of GluN1 with α-actinin, whereas internalization of ICAM-5 peptide perturbed the GluN1/α-actinin interaction. NMDA treatment decreased α-actinin binding to ICAM-5, and increased the binding to GluN1. Proper synaptic distribution of α-actinin requires the ICAM-5 cytoplasmic domain, without which α-actinin tended to accumulate in filopodia, leading to F-actin reorganization. The results indicate that ICAM-5 retards spine maturation by preventing reorganization of the actin cytoskeleton, but NMDA receptor activation is sufficient to relieve the brake and promote the maturation of spines.

ICAM-5: a neuronal dendritic adhesion molecule involved in immune and neuronal functions.

The neuron-specific intercellular adhesion molecule-5 (ICAM-5, telencephalin) is a member of the ICAM family of adhesion proteins. It has a complex structure with nine external immunoglobulin domains followed by a transmembrane and a cytoplasmic domain. The external part binds to beta1- and beta2-integrins and the matrix protein vitronectin, whereas its transmembrane domain binds to presenilins and the cytoplasmic domain to alpha-actinin and the ERM family of cytoplasmic proteins. In neurons it is confined to the soma and dendrites and it is enriched in dendritic filopodia with less expression in more mature dendritic spines. ICAM-5 strongly stimulates neurite outgrowth. ICAM-5 is cleaved by matrix metalloproteases upon activation of glutamate receptors or degraded through endocytosis resulting in increased spine maturation. Ablation of ICAM-5 expression increases functional synapse formation. The cleaved soluble fragment of ICAM-5 is immunosuppressive, which may be important in neuronal inflammatory diseases.