Abstract
The interaction between collagen/collagen-like peptides and the commonly expressed immune cell receptor LAIR-1 (leukocyte-associated immunoglobulin-like receptor-1) regulates and directs immune responses throughout the body. Understanding and designing these interactions within the context of biomaterials could advance the development of materials used in medical applications. In this study, we investigate the immunomodulatory effects of biomaterials engineered to display a human collagen III-derived ligand peptide (LAIR1-LP) that targets LAIR-1. Specifically, we examine the effects of LAIR1-LP functionalized surfaces on uptake of polymeric particles and cell debris by macrophages polarized toward inflammatory or healing phenotypes. We observed that culture of macrophages on LAIR1-LP functionalized surfaces increased their uptake of PLGA micro- and nano-particles, as well as apoptotic fibroblasts, while reducing their secretion of TNFα in response to LPS/IFNγ pro-inflammatory stimulation, when compared to cells seeded on control surfaces. To investigate the role of LAIR-1 in the observed LAIR1-LP-induced effects, we used siRNA to knock down LAIR-1 expression and found that cells lacking LAIR-1 exhibited enhanced particle uptake on LAIR1-LP and control surfaces. Furthermore, analysis of gene expression showed that LAIR-1 knockdown led to increase expression of other receptors involved in cell uptake, including CD-36, SRA-1, and beta-2 integrin. Together, our study suggests that LAIR1-LP enhances macrophage uptake potentially through interactions with collagen-domain binding surface receptors, and inhibits inflammation through interaction with LAIR-1.
Highlights
The extracellular matrix protein collagen plays a complex multifaceted role in regulating cells in the immune system and maintaining homeostasis
ImageStream analyses of images that were obtained at internal focal planes confirmed that the poly(lactic-co-glycolic acid) (PLGA) MPs were successfully taken up by bone marrow derived macrophages (BMDM) (Figure 1C), and >90% of the cells which were gated to have positive fluorescent signal showed MPs that were internalized by cells
LAIR1-LP interaction with leukocyte-associated immunoglobulin-like receptor-1 (LAIR-1) requires a trimeric structure of the peptide (Brondijk et al, 2010) and we confirmed the triple-helical folding of the LAIR1-LP peptides by circular dichroism (Supplementary Figure SI-1)
Summary
The extracellular matrix protein collagen plays a complex multifaceted role in regulating cells in the immune system and maintaining homeostasis It is the most abundant protein in the human body and comes in 29 different varieties, all containing the conserved triple helix suprastructure stabilized by repeated amino acid sequences of glycine-X–Y, where X and Y can be any amino acid but are often proline and hydroxyproline, respectively (Gelse et al, 2003). Adhesion to collagen generally reduces the inflammatory response of macrophages, and is thought to have a critical regulatory role in setting the threshold for innate immune responses in tissue (Meyaard, 2010). These immune inhibitory functions are in part from its interaction with the commonly expressed leukocyte-associated immunoglobulin-like receptor 1 (LAIR-1 or CD305)
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