Low molecular weight polysialic acid binds to properdin and reduces the activity of the alternative complement pathway

Abstract

Sialic acids as the terminal caps of the cellular glycocalyx play an essential role in self-recognition and were shown to modulate complement processes via interaction between α2,3-linked sialic acids and complement factor H. Previously, it was suggested that low molecular weight α2,8-linked polysialic acid (polySia avDP20) interferes with complement activation, but the exact molecular mechanism is still unclear. Here, we show that soluble polySia avDP20 (molecular weight of ~ 6 kDa) reduced the binding of serum-derived alternative pathway complement activator properdin to the cell surface of lesioned Hepa-1c1c7 and PC-12 neuroblastoma cells. Furthermore, polySia avDP20 added to human serum blocked the alternative complement pathway triggered by plate-bound lipopolysaccharides. Interestingly, no inhibitory effect was observed with monosialic acid or oligosialic acid with a chain length of DP3 and DP5. In addition, polySia avDP20 directly bound properdin, but not complement factor H. These data show that soluble polySia avDP20 binds properdin and reduces the alternative complement pathway activity. Results strengthen the previously described concept of self-recognition of sialylation as check-point control of complement activation in innate immunity.

Association of polysialic acid serum levels with schizophrenia spectrum and bipolar disorder-related structural brain changes and hospitalization

“…In microglia, shedding of sialylated proteins 33 occurs upon activation 7,34 , and desialated microglia could facilitate further immune cell and complement activation 35 . Indeed, the desialyation of microglia due to inflammatory activation 6,7 and the sensing of the desialylation by the alternative complement pathway 36 could further support the role of neuroinflammation in schizophrenia 37 especially as neuron-microglia interactions and changes in complement have been implicated in the pathogenesis of schizophrenia 38,39 . Similarly, shedding of polySia-NCAM and other polysialylated structures from neuronal cell surfaces 40 that relate to neural activation or dysfunction, could subsequently lead to increased soluble serum levels of polySia.…”

“…Prospective longitudinal studies including measurements of polySia in cerebrospinal fluid will be necessary to further validate our findings and to further establish a causal relationship between polySia and SZ/SZA and BD. While evidence suggests cross-talk of polySia 30 , 36 , 49 , possibly via an active transport mechanism 11 , 12 , over the blood-CNS barrier, further studies are necessary to better quantify this cross-talk. We have not seen any significant effect of antipsychotic or antidepressant medication on the polySia serum level, but we are aware that this could be a potential confounder.…”

Neuroimmunomodulatory properties of polysialic acid

“…In vitro, LPS-induced deposition of complement was reduced by polySia avDP20 indicating an inhibition of the alternative complement pathway [ 87 ]. This was followed up in a recent study showing that polySia avDP20 directly interacts with properdin, a positive regulator of the alternative pathway, and reduces properdin-mediated complement deposition [ 133 ]. Properdin is an oligomeric protein with an unusually high isoelectric point (> pH 9.5).…”

“…Under physiological conditions, therefore, properdin is highly positively charged, and tends to bind to polyanionic structures such as sulfated glycosaminoglycans on the cell surface or in the extracellular environment [ 134 , 135 ]. This may be the reason, why polyanionic polySia interacts with properdin and why soluble forms of polySia are able to compete with complement activation by properdin at the surface of lesioned cells [ 133 ].…”

Therapeutic potential to target sialylation and SIGLECs in neurodegenerative and psychiatric diseases

“…For instance, complement factor H binds to α2,3-linked sialic acids on the cell surface and is known to bind the opsonin C3b, thereby inhibiting the formation and inducing the disassembly of the alternative C3-convertase (37)(38)(39). Furthermore, low molecular weight polysialic acid has been shown to have the capacity to sequester the positively charged complement protein properdin (40). Experimentally, it prevented activation of the alternative complement pathway and protected susceptible murine hepatoma cells and rat neuroblastoma cells from complementmediated cell death in vitro (40).…”