Cell adhesion is pivotal in normal development and cellular functions. ICAM-5 also known as telencephalin (TLN), a member of the ICAM family of adhesion proteins, holds unique properties compared to other ICAMs. ICAM-5, the largest ICAM identified, is expressed exclusively in telencephalic neurons of the CNS. Its appearance often coincides with dendritic elongation, branching, and synapse formation, suggesting roles beyond immune interactions, potentially in neuronal activity and cognition. This article delves into the structure, expression, and functions of ICAM-5 in the mouse, rabbit, and human contexts, highlighting its distinct characteristics and implications in neurobiology.
Related Products
The immunoglobulin superfamily (IgSF) includes over 100 vertebrate members primarily expressed on cell surfaces, governing functions such as cytoskeletal organization, adhesion, migration, and immune recognition. Intercellular adhesion molecules (ICAMs), a subset of IgSF, bind leukocyte β2 integrins. Of the five ICAM members, ICAM-1 shows broad tissue distribution, while ICAM-2, -3, -4, and -5 exhibit more restricted expression. ICAM-5 is uniquely expressed in telencephalic neurons, implicating it in both immune responses and neuronal functions.
Structure of ICAM-5
ICAM-5, first purified from rabbit telencephalon, belongs to the Ig superfamily with a complex structure comprising nine Ig-like domains. Similar to ICAM-1 and ICAM-3 in its distal domains, ICAM-5's structure and function are extensively conserved across species.
Fig. 1 ICAM-5's structural comparison with ICAM-1, -2, -3, and LW antigen (ICAM-4) (Yang H. 2012).
Mouse ICAM-5
Mouse ICAM-5 is located on chromosome 9, alongside ICAM-1 and -4. Its gene spans approximately 6.3 kb, divided into 11 exons. The protein has a 59-amino-acid cytoplasmic tail, featuring potential phosphorylation sites significant for its function. The Ig-like domains, critical for integrin binding, share high homology with other ICAMs, particularly in domains critical for β2 integrin interaction.
Rabbit ICAM-5
Rabbit ICAM-5 cDNA reveals nine Ig-like domains, highly similar to the mouse counterpart, comprising 3,013 bp. The extracellular region's Ig-like domains, essential for its adhesive functions, are critical for neuronal development. The cytoplasmic domain shares features with cardiac troponin-T2, indicative of its role in cellular signaling.
Human ICAM-5
Mapped to chromosome 19p13.2, human ICAM-5 shares high sequence similarity with mouse and rabbit ICAM-5. Its gene spans 2,772 nucleotides, encoding a protein with a large extracellular domain critical for β2 integrin binding, a transmembrane domain, and a cytoplasmic tail. Functional domains in this protein include conserved glycosylation sites important for its adhesive functions.
Expression of ICAM-5
ICAM-5 is exclusively expressed in the mammalian telencephalon, unlike other ICAMs, confined mostly to immune cells. In the telencephalon, ICAM-5's presence in neuronal subsets and its specific localization to somatodendritic membranes underline its role in neuronal circuit formation.
Mouse ICAM-5 Expression
In mice, ICAM-5 mRNA is restricted to telencephalic neurons, with strong signals in the hippocampus and cerebral cortex. This neuronal-specific expression suggests ICAM-5's crucial role in synaptic development and maintenance.
Rabbit ICAM-5 Expression
In rabbits, ICAM-5 mRNA is primarily found in the telencephalon, with substantial postnatal increases aligning with neuronal development stages. Its absence in non-neuronal tissues further emphasizes its neuron-specific functions.
Human ICAM-5 Expression
Human ICAM-5 is prominently expressed in the hippocampus, cerebral cortex, and basal ganglia. Developmentally, its expression escalates in the late fetal period, paralleling dendritic and synaptic maturation, pointing towards its role in cognitive functions.
Functions of ICAM-5
Immunological Activities
ICAM-5 plays a critical role in the immune system by interacting with β2 integrins like leukocyte function-associated antigen-1 (LFA-1) on leukocytes. This interaction is crucial for the binding and regulation of immune cells in the CNS. For instance, ICAM-5 can induce morphological changes in microglia, the brain's resident immune cells, through interaction with LFA-1, potentially modulating their activity and state in both healthy and pathological conditions.
Furthermore, soluble forms of ICAM-5 (sICAM-5) have been detected in physiological fluids under conditions like brain ischemia, epilepsy, and encephalitis (infection or inflammation of the brain). sICAM-5 has been shown to modulate T cell activation, notably inhibiting the activation of naive T cells while promoting the production of cytokines such as TGF-β1 and IFN-γ. These properties highlight ICAM-5's potential role in maintaining the immune privilege of the brain by preventing excessive immune activation that could lead to inflammatory damage.
Promotion of Neurite Outgrowth
ICAM-5 is intimately involved in promoting neurite outgrowth, particularly during the early stages of neuronal development. It aids in dendritic elongation and branching, essential for forming functional neural networks. In vitro studies have shown that ICAM-5 can promote neurite outgrowth more effectively than other ICAMs, such as ICAM-1. This effect is mediated through homophilic adhesion and interactions with cytoskeletal elements like α-actinin and the ERM (ezrin, radixin, moesin) family of proteins, which link membrane proteins to the actin cytoskeleton.
Synaptic Function and Long-Term Potentiation (LTP)
ICAM-5 is essential for long-term potentiation (LTP), a process underpinning synaptic plasticity and memory formation. Blocking ICAM-5 function significantly impairs LTP at hippocampal synapses, suggesting that ICAM-5-mediated cell adhesion is vital for synaptic strengthening. The reduction in ICAM-5 expression in conditions like Alzheimer's disease (AD) correlates with cognitive decline, linking it to neurodegenerative processes and synaptic dysfunction.
Cognitive Function
ICAM-5's expression patterns and its involvement in synaptic formation and maintenance make it relevant to cognitive functions. In AD, reduced ICAM-5 levels have been observed, particularly in the hippocampus, implicating it in memory impairment and dementia. Moreover, ICAM-5's interaction with presenilins, proteins involved in the pathogenesis of AD, further connects it to cognitive health. The association with presenilins suggests a regulatory role in the processing of amyloid precursor proteins, a critical element in AD pathology.
Conclusion
ICAM-5 exemplifies a unique cell adhesion molecule with significant roles in both the nervous and immune systems. Its exclusive expression in the telencephalon, intricate structure, and multifaceted functions underscore its importance in neuronal development, synaptic plasticity, and immune regulation. Understanding ICAM-5's mechanisms and interactions paves the way for potential therapeutic interventions in neurodegenerative and neuroinflammatory diseases, reinforcing its relevance in maintaining the delicate balance of the CNS.
Reference
- Yang H. Structure, expression, and function of ICAM‐5. International Journal of Genomics. 2012, 2012(1): 368938.
.
