Toll like receptors and chemokine receptors: 2 interconnected arms of the innate immune response.

When we are infected by a virus, or a bacteria, or a parasite, we mount specialised responses called immune responses. At the start of this process, the first thing we have to be able to do is to register the fact that we have been infected. This is achieved using specialised molecules called Toll Like Receptors, which sense the infecting agents and start to initiate an immune response. We have a number of Toll Like Receptors which are specialised in recognising different types of invading organisms. One of the ways in which Toll Like Receptors initiate the immune response is by inducing the synthesis of a different class of molecules called chemokines which are essential in helping to get white blood cells to the infected sites. The white blood cells are important in helping to start the process of destruction of the invading organisms and this results in inflammation developing around the infected sites. Eventually we mount a full immune response to the invading organism and, all being well, this will ensure its removal from our body. We are interested in how the Toll Like Receptor and Chemokine families interact to coordinate our response to infection. Understanding this interaction is central to our understanding of our response to invading organisms and will provide invaluable data that may help us to improve our responses to such agents.

Toll like receptors (TLRs) have emerged as the primary sentinels of microbial infection and the various members of the TLR family bind different microbial products which are collectively referred to as Pathogen Associated Molecular Patterns (PAMPs). In response to binding of ligand, TLRs induce intracellular signalling which results in the rapid upregulation of inflammatory cytokines. This then triggers expression, and release, of inflammatory chemokines which chemoattract inflammatory leukocytes to the infected site. Thus the TLR and chemokine families represent a fundamentally important axis in the initiation of the innate immune response to microbial pathogens. Curiously we, and others, have recently reported that in addition to inducing inflammatory chemokine expression, BLP and LPS (ligands for TLRs2 and 4 respectively) also trigger a rapid transcriptional downregulation of inflammatory chemokine receptor expression whilst not altering expression of constitutive chemokine receptors such as those involved in lymph node homing of leukocytes. We hypothesise, therefore, that, as is seen with TLR4 signalling in dendritic cells, signalling through TLR2, and probably other TLRs induces a shift in chemokine receptor expression from inflammatory receptors required for getting inflammatory leukocytes into infected sites, to lymph node homing receptors, aimed at getting the leukocytes from the inflamed sites to the draining lymph nodes. Thus effectively TLR signalling within an infected/inflamed tissue will regulate the time spent by a variety of leukocyte subtypes within the inflamed environment. We now propose to carefully examine the regulatory relationship between the TLR and chemokine receptor families in the hope that this will provide a more detailed understanding of the nature of this relationship and of its physiological importance. Specifically, we propose to examine the breadth of chemokine receptors that are regulated by TLR signalling. In addition we propose to examine which of the TLRs are capable of mediating this regulation of chemokine receptor expression. We also propose to use real-time imaging technology, and other approaches, to formally test the hypothesis that the primary function of TLR-induced chemokine receptor regulation is to limit the residency time of inflammatory leukocytes in the infected sites and to promote lymph node homing of, and antigen presentation by, these leukocytes.