CD22 Blockage Restores Age-Related Impairments of Microglia Surveillance Capacity

Abstract

Microglia, the innate immune cells of the brain, are essential for maintaining homeostasis by their ramified, highly motile processes and for orchestrating the immune response to pathological stimuli. They are implicated in several neurodegenerative diseases like Alzheimer’s and Parkinson’s disease. One commonality of these diseases is their strong correlation with aging as the highest risk factor and studying age-related alterations in microglia physiology and associated signaling mechanism is indispensable for a better understanding of age-related pathomechanisms. CD22 has been identified as a modifier of microglia phagocytosis in a recent study, but not much is known about the function of CD22 in microglia. Here we show that CD22 surface levels are upregulated in aged versus adult microglia. Furthermore, in the amyloid mouse model PS2APP, Aβ-containing microglia also exhibit increased CD22 signal. To assess the impact of CD22 blockage on microglia morphology and dynamics, we have established a protocol to image microglia process motility in acutely prepared brain slices from CX3CR1-GFP reporter mice. We observed a significant reduction of microglial ramification and surveillance capacity in brain slices from aged versus adult mice. The age-related decrease in surveillance can be restored by antibody-mediated CD22 blockage in aged mice, whereas surveillance in adult mice is not affected by CD22 inhibition. Moreover to complement the results obtained in mice, we show that human iPSC-derived macrophages exhibit an increased phagocytic capacity upon CD22 blockage. Downstream analysis of antibody-mediated CD22 inhibition revealed an influence on BMP and TGFβ associated gene networks. Our results demonstrate CD22 as a broad age-associated modulator of microglia functionality with potential implications for neurodegenerative disorders.

Aging microglia

“…Genetic ablation or inhibition through anti-CD22 injection in mice robustly promoted the clearance of myelin debris, rescued the age-related microglial signature and improved cognitive functions [34]. Furthermore, these changes were accompanied by increased microglia surveillance and motility and a restoration of microglia homeostatic morphology, as observed via twophoton imaging [35]. Notably, CD22 is also expressed and secreted by mouse neurons, exerting an inhibitory role on microglia in soluble form [36].…”

“…In addition to their heightened responsiveness to stimulation and altered morphology, further alterations have been described in aged microglia, such as their reduced ability to scavenge the brain parenchyma to remove neuronal debris, apoptotic bodies and secreted proteins through phagocytosis [32,33]. One of the responsible factors is CD22, a negative regulator of microglia phagocytosis [34,35], whose expression in microglia in the CNS increases with age. Genetic ablation or inhibition through anti-CD22 injection in mice robustly promoted the clearance of myelin debris, rescued the age-related microglial signature and improved cognitive functions [34].…”

Phagocytic microglia and macrophages in brain injury and repair

“…In addition to the aforementioned receptors, other receptors may also regulate microglial phagocytosis. For example, CD22 (Siglec 2) is a negative regulator of phagocytosis and its expression is upregulated on aged microglia 86,87 . CD22 also mediates the antiphagocytic effect of α2,6‐linked sialic acid, and inhibition of CD22 promotes clearance of myelin debris, amyloid‐β oligomers, and α‐synuclein fibrils in vivo 86,88 .…”

“…For example, CD22 (Siglec 2) is a negative regulator of phagocytosis and its expression is upregulated on aged microglia. 86 , 87 CD22 also mediates the antiphagocytic effect of α2,6‐linked sialic acid, and inhibition of CD22 promotes clearance of myelin debris, amyloid‐β oligomers, and α‐synuclein fibrils in vivo. 86 , 88 Long‐term CNS delivery of an antibody that blocks CD22 function reprograms microglia toward a homeostatic transcriptional state and improves cognitive function in aged mice.…”

Human brain sialoglycan ligand for CD33, a microglial inhibitory Siglec implicated in Alzheimer’s disease

“…2 ), where Siglec-8 and Siglec-10 dominate quantitatively ( 16 , 17 ). Although Siglec-2 (CD22) was linked to microglial function in aging mice ( 30 , 31 ), its expression was not reported in human microglia ( 17 , 32 ). Siglec-1, which is thought to mediate some types of phagocytosis ( 33 ), was the only Siglec whose gene expression was different (reduced) in AD microglia compared with no dementia microglia.…”