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CLLP the Wings of Inflammation: An Investigation of Immunomodulatory Collagen-mimetic LAIR-1 Ligand Peptides


Persistent inflammatory stimuli can result in chronic inflammation and ultimately disease states such as, rheumatoid arthritis and Alzheimer’s Disease. Typical therapeutic approaches have failed to resolve chronic inflammation in patients. Therefore, this proposal will investigate an alternative strategy of immunomodulatory biomaterials, specifically a deliverable collagen-mimetic peptide that has been engineered as a high affinity ligand for the inhibitory immune receptor LAIR-1, named Collagen-mimetic LAIR-1 Ligand Peptide (CLLP). The hypothesis of this research is that interactions between CLLP and LAIR-1 expressing immune cells, be it through functionalized biomaterials or particle delivery vehicles, will result in suppressed inflammatory activation, furthermore phagocytes seeded on CLLP surfaces will experience increased uptake (dictated in part by the extent of LAIR-1 expression). When investigating CLLP’s effect on inflammatory activation of macrophages and dendritic cells it was observed that LAIR-1 expressing cells were significantly inhibited in their inflammatory activation when seeded onto CLLP surfaces. In contrast, when investigating cells that had naturally low LAIR-1 expression or cells with significantly reduced LAIR-1 expression, via siRNA knockdown, CLLP failed to reduce inflammatory activation. Furthermore, both macrophages and dendritic cells experienced increases in uptake on CLLP functionalized surfaces. The results of these uptake experiments also strongly suggest that LAIR-1 is inhibitory to uptake and the observed CLLP induced increases in uptake are not due to LAIR-1 signaling. When dendritic cells are seeded on CLLP surfaces and stimulated with antigen functionalized nanoparticles, the cells exhibit increased antigen presentation. When CLLP was delivered to cells via nanoparticles it successfully inhibited macrophage activation. Interestingly functionalizing nanoparticles with CLLP significantly reduced the uptake of said particles by LAIR-1 expressing phagocytes. The immunomodulatory strategy of CLLP functionalization could potentially be broadly applied, for example toward the development of device coatings, anti-inflammatory particle-based therapeutics, and/or integrated biomaterials

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