Signal Inhibitory Receptor on Leukocytes-1 (SIRL-1)

Summary

In this thesis, we aimed to better understand the role of the immune inhibitory receptor Signal Inhibitory Receptor on Leukocytes-1 (SIRL-1) in neutrophil functions. Inhibitory receptors play a crucial role in tailoring immune responses. SIRL-1 belongs to a family of transmembrane receptors, the Ig superfamily, and is mainly expressed on granulocytes and monocytes. SIRL-1 contains two immunoreceptor tyrosine-based inhibitory motifs (ITIMs) in its cytoplasmic domain and recruits the phosphatases SHP-1 and SHP-2 in pervanadate-treated cells. However, it remains unclear which host ligand(s) associates with and regulates SIRL-1 function. Furthermore, physiological functions of the inhibitory receptor SIRL-1 in the immune response have not been studied. Neutrophils express SIRL-1 on their surface and engagement of SIRL-1 attenuates degranulation induced by juxtaposed FcεRI, the immunoreceptor tyrosine-based activation motif (ITAM)-coupled IgE receptor, in a basophilic cell line. We investigated whether SIRL-1 could control one of the most important engines of destruction by neutrophils: the respiratory burst. In addition to producing classical effector molecules, such as reactive oxygen species (ROS) and lytic enzymes, neutrophils can extrude neutrophil extracellular traps (NETs), a unique ability related to the pathogenesis of systemic lupus erythematosus (SLE). Therefore, we investigated the effect of SIRL-1 ligation on the release of NETs in a cohort of patients with SLE. An intriguing question that has remained unanswered is whether SIRL-1 could affect signaling relayed by other receptors besides FcRs, such as Toll-like receptors (TLRs). We evaluated SIRL-1-regulated suppression of neutrophil activation induced by receptors for other danger signals, such as TLRs. To subvert the functions of pattern recognition receptors (PRRs) or FcRs, bacterial pathogens use virulence factors to exploit inhibitory signaling and promote their adaptive fitness. This ingenious bacterial strategy of immune evasion is reviewed. One way in which bacteria could undermine host defense is through molecular mimicry of host ligands by microbial structures to activate inhibitory receptors. We explored whether bacteria could have evolved to engage the immune inhibitory receptor SIRL-1.

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