The receptor–receptor interactions within the cytokine receptor superfamily. Role in neuroinflammation and beyond

The mild encephalitis (ME) hypothesis of schizophrenia characterized a subgroup of severe psychiatric disorders in which low level neuroinflammation casually underlies the disorder as the core pathogenic mechanism. This low level neuroinflammation prevails and is important during a critical time period of diseases and it thought to be especially relevant in affective and schizophrenic disorders. The aetiologies involved in low level neuroinflammation vary, including infections, autoimmunity, toxicity and trauma. The pathological mechanisms generally are linked to the interactions between brain cells, immune cells and solutes resulting in an effective inflammatory immune response (IIR). The IIR first requires the recruitment of cells to the site of inflammation and then their appropriate activation and regulation. Chemokines and cytokines are critical in these responses since they are both chemotactic and immunoregulatory molecules. Cytokines are immunomodulating agents such as interleukins, interferons and chemokines which regulate the response to infection, inflammation and trauma. Each cytokine has a matching cell-surface receptor which varies in their threedimensional structure and cell type location. For instance, the cytokine receptor family comprises the Immunoglobulin (Ig) receptor superfamily, the Hemopoietic growth factor (type 1) receptor family, the interferon (type 2) receptor family, the tumor necrosis factor (TNF) (type 3) receptor family, the interleukin-17 and -12 (IL-17 and IL-12) receptor family and the class A G protein-coupled receptor chemokine receptor family. All these receptor-ligand pairs have a fundamental role in providing directional cues for the immune cell trafficking and signaling, both in the context of homeostasis and disease. However, immunomodulatory agents and their receptors are not isolated entities, but instead function in complex networks involving homo- and heteroreceptor complexes formation as well as crosstalk with other signaling cascades. For example, the arrest and chemotaxis of leukocytes during homeostasis and inflammation is an orchestrated phenomenon by a multitude of cytokines which are particularly adept at adjusting rapidly to changes within the environment. The confrontation of leukocytes with different combinations of chemokines that are concomitantly produced under physiological or pathological conditions in vivo is a complex challenge and receptor–receptor interaction in heteroreceptor complexes could be the molecular mechanisms behind this phenomenon. In viral-induced disease receptor–receptor interactions between viral and host-coded receptors can have a special relevance. Growing evidence indicates that the homo/heterodimeric form is the basic functional structure of cytokine receptors. These receptor families are not isolated entities that are activated following ligand binding. Rather, they exist as heteroreceptor complexes and/or higher order oligomers at the cell surface, even in the absence of ligands. These heteroreceptor complexes form organized receptor networks that can be modified by changes in receptor expression and ligand levels, indicating their dynamic properties. The way in which these receptor complexes are altered into new states determine their ligand binding, their pharmacological properties and the signal. These conformations thus represent a fundamental mechanism which increases the broad diversity of cytokine receptor functions. Understanding these heteroreceptor complexes and their dynamics at the cell surface is thus critical for influencing cytokine/chemokine functions. Modulation of cytokine including chemokine receptor activities through these molecular mechanisms has significant implications for physiological and pathological processes in the immune system. It could open up new possibilities for drug discovery and drug efficacy. For instance, small interfering synthetic peptides of TM regions of cytokine/chemokinereceptorsmayinterferewiththeformation of oligomeric receptor complexes and inhibit functional activity of the receptors. Therefore, small interfering TM peptides and possibly compounds that target cytokine heteroreceptor complexes are proposed to have therapeutic applications.