Microglial immunoreceptor tyrosine-based activation and inhibition motif signaling in neuroinflammation

Abstract

Elimination of extracellular aggregates and apoptotic neural membranes without inflammation is crucial for brain tissue homeostasis. In the mammalian central nervous system, essential molecules in this process are the Fc receptors and the DAP12-associated receptors which both trigger the microglial immunoreceptor tyrosine-based activation motif- (ITAM-) Syk-signaling cascade. Microglial triggering receptor expressed on myeloid cells-2 (TREM2), signal regulatory protein-beta1, and complement receptor-3 (CD11b/CD18) signal via the adaptor protein DAP12 and activate phagocytic activity of microglia. Microglial ITAM-signaling receptors are counter-regulated by immunoreceptor tyrosine-based inhibition motif- (ITIM-) signaling molecules such as sialic acid-binding immunoglobulin superfamily lectins (Siglecs). Siglecs can suppress the proinflammatory and phagocytic activity of microglia via ITIM signaling. Moreover, microglial neurotoxicity is alleviated via interaction of Siglec-11 with sialic acids on the neuronal glycocalyx. Thus, ITAM- and ITIM-signaling receptors modulate microglial phagocytosis and cytokine expression during neuroinflammatory processes. Their dysfunction could lead to impaired phagocytic clearance and neurodegeneration triggered by chronic inflammation.

Figure 1

ITAM-/ITIM-signaling cascade. Left side: Upon ligand binding, activatory receptors like TREM2, SIRPβ1, FcγRI or FcγRIIIA associate with ITAM containing adaptor proteins such as DAP12 or the common γ chains through interactions between charged amino acids (−/+) within the transmembrane regions of each protein. Subsequently, members of Src kinase family (SKF) phosphorylate tyrosine residues of ITAMs. Phosphotyrosine residues are docking sites for Syk protein kinases that upon activation mediate cellular activation via a number of downstream cascades. Right side: Upon ligand binding, inhibitory receptors like most Siglecs recruit SHP1 and SHP2 which can in turn terminate intracellular signals emanating from ITAM receptors.