Siglec Modulation of Inflammatory Responses

University Of California, San Diego, La Jolla CA

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Abstract

Sialic acids (Sias) are negatively-charged sugars on cell surface or secreted molecules. Several Sia biological roles involve Sia-recognizing receptors called Siglecs (Sia-recognizing Ig-like lectins). Many of the CD33-related subset of Siglecs (CD33rSiglecs) on innate immune cells appear to recognize host Sias as self, dampening inflammatory reactivity via cytosolic Immunoreceptor Tyrosine-Based Inhibitory Motifs (ITIMs). However, bacteria expressing Sias can hijack these Siglecs, to suppress innate immune responses. Another subset of CD33rSiglecs lack ITIMs and instead recruit the Immunoreceptor Tyrosine- Based Activatory Motifs (ITAMs) of DAP-12. The functions of activatory Siglecs are unknown. Also unexplained are CD33rSiglecs that undergo lineage-specific mutations of an amino-terminal V-set domain critical Arg residue required for Sia recognition. The overall hypothesis is that the activatory and Arg-mutated versions of CD33rSiglecs represent evolutionary adjustments of inflammatory responses of innate immune cells, faced with pathogens expressing surface Sias that can subvert inhibitory Siglecs. As with several Siglec mutations, many of these Sia-expressing pathogens are human-specific. Some questions can be addressed by comparisons of innate immune cells from human and great ape blood. However, given practical, fiscal and ethical issues, we wil use transgenic mice as models. On a more fundamental level, these studies will address the general significance of mammalian activatory and Arg-mutated Siglecs in modulating the set-state of the myelomonocytic cell innate immune response, and the inflammatory response to bacterial pathogens bearing Sias. Specific aims include: generating and studying mice with transgenic expression of native or arginine-mutated human Siglec-9 or with combinations of activatory and/or inhibitory forms of Siglec-E on neutrophils, monocytes and macrophages; comparing human and chimpanzee innate immune cells with different combinations of activatory/lnhibitory and or Arg-mutated forms of Siglec-5 and Siglec-14; and finally, comparing the interactions of innate immune cells from the above studies with certain pathogenic bacteria that express sialic acid mimics of Siglec ligands.