Chemokine receptors redundancy

Analysis of mouse models with genetic disruption of individual chemokines or chemokine receptors has usually revealed specific phenotypes, but generally, only under stressed conditions (infection, allograft, etc.), which suggests that the full potential of chemokine-receptor redundancy may not always be realized in vivo. Instead, under normal physiological conditions and during immune responses, chemokines and chemokine receptors appear to function as a coordinated, but vulnerable, network. 

The apparent contradiction between inflammatory chemokine and chemokine receptor redundancy observed in vitro and specific phenotypes revealed from gene-targeted animals can be resolved if one considers that these chemokines and their receptors function as a cooperative network in vivo to generate a complete immune response. Cooperation exists by coordinating the temporal expression of chemokine receptors on different cell types, the same cell type, or even the same cell. 

Until recently, it has been difficult to dissect the relative role of each che-mokine in the inflammatory processes leading to allograft rejection, especially as many chemokines and chemokine receptors are seemingly redundant (2,8). Indeed, during allograft rejection, the expression of many chemokines and chemokine receptors can be detected in the allograft—only a few of which represent viable targets for therapeutic intervention (5,6). 

Chemokines are redundant in their action on target cells. Furthermore, a given leukocyte population usually has receptors for and responds to different molecules (Table 3). For example, macrophages respond to the widest range of chemokines... 

Chemokines constitute a large family of about 50 proteins that interact with about 20 different receptors. Cbemokines play a crucial biological role in inflammation, immunity and viral infection. In spite of certain degree of redundancy, the chemokine system presents several levels of specificity in terms of receptor interaction, target cells and biological functions. The relevance of certain chemokines in specific immune responses is also suggested by the expression of selected chemokine-like proteins or chemokine-receptors by viruses as way to escape host response. 

The role that chemokines play in the localization of blood or lymphatic-borne-T lymphocytes near lymph nodes is incompletely understood. Transgenic mice that lack expression of specific chemokines have not been illustrative, suggesting that the process is the result of stimulation by multiple chemokines with overlapping receptor affinity or that the essential chemokine-receptor complex has not yet been identified. Ligand and receptor redundancy is common in chemokine networks. However, after the T lymphocyte has responded to the complex array of chemotactic signals and arrived at the lymph node, the events by which it migrates through the endothelium into the lymph node itself are well characterized. 

The redundancy and cross talk between chemokines and receptors in vivo creates a complex immunologic and regulatory communication system. As proposed by Rot and von Andrian (14), our challenge is therefore to understand... 

Chemokines are major mediators of leukocyte recruitment and activation that occur in response to microbial invasion of the respiratory tract. The ELR CXC chemokines and their receptors are required for neutrophil-dependent innate responses against bacterial, fungal, and mycobacterial pathogens. While some redundancy in ELR CXC chemokine function exists, there is evidence of tissue-specific chemokine responses that may be required for the recruitment of neutrophils to selective compartments of the lung. ELR CXC chemokines can also participate in the afferent limb of immune responses via the recruitment of neutrophils, which serve to polarize toward the development of protective T-1 cell-mediated immune responses. The ELR CXC chemokines and CC chemokines. 

Antagonism of chemokines and their receptors represents an attractive and potentially effective means of modulating inflammatory responses, and it may prove to be a useful therapeutic strategy for atherosclerosis and many other inflammatory diseases. Successful therapeutic intervention is based on selective disease modification with minimal impact on the normal physiological processes so as to limit the side effects of treatment. Due to the complexity of the chemokine hemokine receptor system, the inherent redundancy... 

There are, however, a number of caveats that require consideration. There is still only a partial understanding of the complex biology of the chemokine family and its receptors, a situation contributed to by the considerable redundancy of binding of various structurally related chemokines by many of the known receptors. The role of chemokines in various disease states is incompletely known, and the consequences of receptor blockade are similarly not fully established, partly due to the difficulty of producing suitable animal models. 

---