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Title: SOCS and Siglecs : regulation and therapeutic targeting of the pro-inflammatory response
Author: Spence, Shaun
ISNI:       0000 0004 2722 774X
Awarding Body: Queen's University Belfast
Current Institution: Queen's University Belfast
Date of Award: 2011
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Here presented is an account of the polarised inflammatory responses of macrophages in the absence of SOCS2 and SOCS3, which are fixed and dominant compared to wild type. In this setting, SOCS2-1- macrophages upregulate Ml genes and cytokines in response to pro- and anti-inflammatory stimuli, whilst socs3LysMcre macrophages up-regulate only M2 associated responses. Our investigations show that macrophages are unable to polarise towards an Ml phenotype in the absence of SOCS3, whilst the absence of SOCS2 enhances Ml polarisation at the expense of M2. We show these antipodal polarised responses correlates to altered cell recruitment of T-regulatory cells through distorted chemokine production. We note marked alterations in both STAT signalling and promoter binding, and NF1C~ signalling and translocation. Interestingly, the absence of SOCS2 or SOCS3 has a profound effect on Siglec-E expression on macrophages. Siglec-E is undetectable in the absence of SOCS2, whilst it is up regulated in the absence of SOCS3. As an inhibitory receptor, the increased presence or absence of Siglec-E correlated well to alterations in LPS-induced cytokine responses. This thesis indicates that a lack of Siglec-E is marked by clearly exaggerated and elevated pro-inflammatory responses. This is seen both, in the absence of SOCS2, and by shRNA knockdown in vitro. Also, we show that elevated levels of Siglec-E, as present in socs3LysMcre macrophages, or an increase in Siglec-E activation leads to a decreased pro- inflammatory responses. In order to exploit this latter point, Siglec ligand (sialic acid)-conjugated poly-lactic (eo-glycolic) acid (PLGA) nanoparticles were employed in a number of models, all of which resulted in attenuated inflammation. Preliminary investigation of Human macrophages shows similar trends on treatment with sialic acid-conjugated nanoparticles, leading to attenuation of LPS- induced endotoxin shock responses, suggesting that these nanoparticles could have wide and far- reaching applications in the treatment of inflammatory disease.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available