Siglec functions of microglia

Abstract

Microglia are the resident immune cells of the central nervous system. They can sense intact or lesioned cells and then respond in an appropriate way. Therefore, microglia need recognition receptors that lead to either the activation or the inhibition of the immune response pathways. Most Siglecs contain an immunoreceptor tyrosine based inhibition motif and its signaling leads to the termination of signals emerging from immunoreceptor tyrosine-based activation motif-signaling receptors. Pro-inflammatory immune responses and phagocytosis are turned down in microglia by inhibitory Siglec signaling. Recently, it was demonstrated that inhibitory Siglecs have neuroprotective effects on cultured neurons by preventing the phagocytosis-associated oxidative burst. Furthermore, microglial mouse Siglec-E and human Siglec-11 have been shown to prevent neurotoxicity via interaction with sialic acid exposed on the neuronal glycocalyx. Thus, Siglecs sensing the intact glycocalyx of neighboring cells keep microglia in a silent homeostatic status.

Opposing Functions of Microglial and Macrophagic TNFR2 in the Pathogenesis of Experimental Autoimmune Encephalomyelitis

“…The impaired ability of TNFR2 deficient microglia to respond to danger signals is reflected in the altered expression of the sensome genes, especially those required for detection of endogenous signals. This includes P2 purinergic receptors, which respond to ATP released by degenerating cells (Rodrigues et al, 2015), and Siglecs that keep microglia in a silent homeostatic status (Linnartz-Gerlach et al, 2014). Together, these data indicate that TNFR2 is an important signal for host defense and proper microglial response to injury.…”

Siglec-mediated regulation of immune cell function in disease

“…They are thought to play a protective role by removal of senile plaques and damaged neurons, but in some conditions they can also exacerbate inflammatory conditions and be neurotoxic 73 . Microglia express a number of Siglecs including CD33, Siglec-11 and Siglec-16 in humans, and CD33, Siglec-E, Siglec-F, and Siglec-H in mice, several of which have been associated with pathology in neurodegenerative diseases 8, 74–78 .…”

“…1f), which leads to suppression of an inflammatory response by preventing excessive uptake of apoptotic neuronal debris 78 . Expression of Siglec-F and Siglec-H under inflammatory conditions has also been proposed to regulate microglial function 78 .…”

“…1f), which leads to suppression of an inflammatory response by preventing excessive uptake of apoptotic neuronal debris 78 . Expression of Siglec-F and Siglec-H under inflammatory conditions has also been proposed to regulate microglial function 78 . Although, recent studies show that several Siglecs have the potential to play preventative or causative roles in neurodegeneration, further studies are needed to gain a clear understanding of how Siglecs regulate functions of resident and activated microglia and inflammatory monocytes in neurodegenerative diseases.…”

C1q: A fresh look upon an old molecule

“…Interestingly, in the presence of other complement components the removal or loss of sialic acid on neuronal membranes results in binding of C1 via C1q, activation of complement, deposition of C3b on the neurons and subsequent ingestion of those membranes by microglia via CR3, the receptor for C3b/iC3b (Linnartz et al, 2012). How CD33, a sialic acid binding negative regulator of the immune system that is expressed on human microglia and that can interact with C1q (as described above), influences this activity, if at all, remains to be defined (reviewed in (Linnartz-Gerlach et al, 2014)). It is firmly established both in vitro and in vivo that fibrillar (beta sheet fibrils) Aβ (fAβ) which accumulate in Alzheimer’s disease (AD) can activate both the alternative and the classical complement pathways in the absence of antibody.…”