During inflammation, circulating polymorphonuclear neutrophils (PMNs) receive signals to cross the endothelial barrier and migrate through the extracellular matrix (ECM) to reach the injured site. Migration requires complex and poorly understood interactions of chemokines, chemokine receptors, ECM molecules, integrins, and other receptors. Here we show that the ECM protein lumican regulates PMN migration through interactions with specific integrin receptors. Lumican-deficient (Lum(-/-)) mice manifest connective tissue defects, impaired innate immune response, and poor wound healing with reduced PMN infiltration. Lum(-/-) PMNs exhibit poor chemotactic migration that is restored with exogenous recombinant lumican and inhibited by anti-lumican antibody, confirming a role for lumican in PMN migration. Treatment of PMNs with antibodies that block beta(2), beta(1), and alpha(M) integrin subunits inhibits lumican-mediated migration. Furthermore, immunohistochemical and biochemical approaches indicate binding of lumican to beta(2), alpha(M), and alpha(L) integrin subunits. Thus, lumican may regulate PMN migration mediated by MAC-1 (alpha(M)/beta(2)) and LFA-1 (alpha(L)/beta(2)), the two major PMN surface integrins. We detected lumican on the surface of peritoneal PMNs and not bone marrow or peripheral blood PMNs. This suggests that PMNs must acquire lumican during or after crossing the endothelial barrier as they exit circulation. We also found that peritoneal PMNs do not express lumican, whereas endothelial cells do. Taken together these observations suggest a novel endothelial lumican-mediated paracrine regulation of neutrophils early on in their migration path.
"They are also involved in collagen fibril growth, fibril organization and ECM assembly (Chen et al. 2010; Chen and Birk 2013). SLRPs also regulate cell-matrix-interactions: for example, lumican modulated cell migration by binding to integrins (Lee et al. 2009; Zeltz et al. 2010); while decorin inhibited cell adhesion to fibronectin and thrombospondin (Winnemoller et al. 1991; Merle et al. 1997). Further, SLRPs have important role in modulation of inflammation (Moreth et al. 2012), and can regulate corneal wound healing (Mohan et al. 2011). "
[Show abstract][Hide abstract] ABSTRACT: Several studies have established the role of activated corneal keratocytes in the fibrosis of the cornea. However, the role of keratocytes in maintaining the structural integrity of a normal cornea is less appreciated. We focus on the probable functions of integrins in the eye and of the importance of integrin-mediated keratocyte interactions with stromal matrix in the maintenance of corneal integrity. We point out that further understanding of how keratocytes interact with their matrix could establish a novel direction in preventing corneal pathology including loss of structural integrity as in keratoconus or as in fibrosis of the corneal stroma.
Journal of Cell Communication and Signaling 03/2014; 8(2). DOI:10.1007/s12079-014-0230-1
"Specifically, lumican was detected on the surface of peritoneal PMNs and not bone marrow or peripheral blood PMNs. This suggests that PMNs must acquire lumican during or after crossing the endothelial barrier as they exit circulation (Lee et al., 2009a,b). Indeed in a cornea model, lumican has a stimulatory role in the process of extravasation of PMNs during the early inflammatory phase present in the healing of the corneal epithelium following debridement (Hayashi et al., 2010). "
[Show abstract][Hide abstract] ABSTRACT: The consecutive steps of tumor growth, local invasion, intravasation, extravasation and invasion of anatomically distant sites are obligatorily perpetrated through specific interactions of the tumor cells with their microenvironment. Lumican, a class II small leucine-rich proteoglycans (SLRP) has been designated key roles both in extracellular matrix (ECM) organisation and as an important modulator of biological functions. This review will critically discuss lumicans' roles in tumor development and progression. We will especially focus on correlating lumicans' expression and distribution in tumor tissues with: (1) the organization of the tumor matrices; (2) tumor cell signaling and functions; (3) tumor cell-matrix interface; (4) tumor angiogenesis; and (5) lumicans potential roles in tumor-associated inflammatory response. Present knowledge of lumicans' biology provides a fundamental platform upon which to build and deepen our understanding of lumican function in tumorigenesis in order to be able to design credible anti-tumor approaches.
Matrix biology: journal of the International Society for Matrix Biology 09/2013; 35. DOI:10.1016/j.matbio.2013.09.003 · 5.07 Impact Factor
"But lumican-integrin interactions are different among different cell types. As reported, lumican promotes neutrophil migration by interaction with integrin β2 , while it inhibits melanoma cell migration through integrin α2β1 , . In human umbilical vein endothelial cells, lumican blocks α2β1 integrin-mediated pro-angiogenic activity . "
[Show abstract][Hide abstract] ABSTRACT: Lumican is a dermatan sulfate proteoglycan highly expressed in connective tissue and has the ability to regulate collagen fibril assembly. Previous studies have shown that lumican is involved in wound healing, but the precise effects of lumican on reepithelialization and wound contraction, the two pivotal aspects of skin wound healing, have not been investigated. Here we explored the roles of lumican in fibroblast contractility, a main aspect of skin wound healing, by adopting mice skin wound healing model and the corresponding in vitro cellular experiments. Our results showed that lumican can promote skin wound healing by facilitating wound fibroblast activation and contraction but not by promoting keratinocyte proliferation and migration. Silencing of integrin α2 completely abolished the pro-contractility of lumican, indicating lumican enhances fibroblast contractility via integrin α2. Our study for the first time demonstrated that lumican can affect fibroblast's mechanical property, which is pivotal for many important pathological processes, such as wound healing, fibrosis, and tumor development, suggesting that lumican might have a potential to be used to modulate these processes.
PLoS ONE 06/2013; 8(6):e67124. DOI:10.1371/journal.pone.0067124 · 3.23 Impact Factor
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