CCR5 Signaling in Macrophages


Pathway Description

Chemokine-CC Motif-Receptor-5 (CCR5) is a member of the GPCR superfamily. It regulates leukocyte chemotaxis in inflammation and serves as a coreceptor for Macrophage-tropic (M-tropic) HIV entry. It serves as a functional receptor for various inflammatory CC-chemokines, including MIP1α/β and RANTES, and is the main coreceptor for M-tropic HIV1 strains. CCR5 is expressed in lymphoid organs such as thymus and spleen, as well as in peripheral blood leukocytes, including macrophages and T-Cells. M-tropic HIV infection of primary human T-Cells and macrophages requires optimal cell surface expression of CCR5 in addition to CD4.Cells expressing CCR5 bind MIP1α, MIP1β and RANTES with high affinity and generate inositol phosphates in response to these chemokines. Chemokine-induced activation of CCR5 promotes the recruitment of GRKs to the plasma membrane, and GRKs mediate the serine phosphorylation of the carboxyl-terminal tail of CCR5. Binding of a ligand (a chemokine or HIV-1) to these receptors induces a characteristic Ca2+ influx and tyrosine phosphorylation. Calcium influx from the extracellular space is mediated by CRAC, ion channels that are activated by calcium release. Calcium release is facilitated by the Gαq through activation of PLC-γ, production of IP3 and diacylglyceral (DAG). Elevated intracellular free Ca2+ is required for activation of calmodulin and the subsequent downstream activation of PYK2, a focal adhesion-associated protein kinase.

CCR5 is also the principal coreceptor of HIV that, in concert with CD4, mediates the binding of the viral envelope (GP120/ENV) protein to the cell surface, allowing subsequent entry into target cells. CD4 binding triggers conformational changes in GP120, which leads to an increased affinity for the coreceptor CCR5 present in the same membrane region. Interaction with CCR5 results in membrane fusion and viral entry. CCR5 stimulation by GP120 activates protein kinase pathways in primary macrophages through preduction of DAG and activation of PKC. The pathway activates the focal adhesion-related kinase PYK2, activates ionic signaling responses, and stimulates phosphorylation of p38 MAPK and JNK. The JNK and p38 MAPK pathways lead to the activation of c-Fos and c-Jun genes, and the consequent induction of β-chemokine secretion. GP120 stimulation of macrophages induces the production of both MIP1β and MCP1, potent chemoattractants for monocytes and macrophages. Ionic signaling responses are modulated by PYK2 activation. Intracellular Calcium elevation mediated by CRAC channels is a principal link between CCR5 stimulation and PYK2 activation in macrophages. In T-Cells, GP120 activation of the chemokine receptors results in elevation of Calcium and activation of Lck, ZAP70, PYK2 and FAK as well as the ERK/MAPK pathway.

HIV infection is associated with immunosuppression caused by a dramatic decrease in the helper T-Cell population. HIV-infected macrophages induce the selective apoptosis of CD4+ T-Cells through Fas-FasL interactions. Cross-linking of CD4 along with TCR-CD3 comlex on the T-Cell surface is involved in upregulation of Fas and sensitization of T-Cells to apoptosis induced by the Fas-FasL interaction. CCR5 is thought to be involved in the recruitment of leukocytes in a growing number of inflammatory diseases, such as rheumatoid arthritis, multiple sclerosis, and asthma, and it plays a major role in AIDS pathogenesis.