Figure 4. Opposing effects of low- and high-avidity ligation of ITAM-coupled receptors are mediated by differential engagement of signalling pathways.

(a) Macrophages sense the cell and tissue environment through interactions of immunoreceptor tyrosine-based activation motif (ITAM)-coupled receptors with low-avidity ligands. Examples include ligation of triggering receptor expressed on myeloid cells 2 (TREM2) by its tissue-expressed ligand semaphorin 6D and as yet unknown macrophage-expressed ligands and of Fc receptors (FcRs) by monomeric immunoglobulin G (IgG) in the serum. This low-avidity signal is tranduced through spleen tyrosine kinase (SYK), phospholipase Cγ (PLCγ) and inositiol-1,4,5-triphosphate (InsP₃) to modulate calcium concentrations and thus regulate the basal activity of calmodulin-dependent kinase (CaMK), protein tyrosine kinase 2 (PYK2) and calcineurin that modulate Toll-like receptor (TLR) and cytokine-mediated responses to make them appropriate for the cell environment. (b) Dramatic and acute changes in the environment (for example, formation of immune complexes that bind FcRs during infection) can lead to high-avidity ligation of ITAM-coupled receptors and strong activation of protein kinase C (PKC), mitogen-activated protein kinases (MAPKs) and nuclear factor-κB (NF-kB). The switch to a PKC-, MAPK- and NF-κB-dominant signal promotes synergy with TLRs and inhibits cytokine signalling.