A Site on Laminin α5, AQARSAASKVKVSMKF, Induces Inflammatory Cell Production of Matrix Metalloproteinase-9 and Chemotaxis

Abstract

Several peptide sequences in laminin α1, the α-chain of laminin (Ln)-1, mediate biological responses in vitro, but Ln-1 is rare in vivo. Since Ln-5 and Ln-10, which contain the α3 and α5 chains, respectively, are the most prominent laminin heterotrimers in normal adult tissues and few functional domains in other laminin chains have been identified, we are investigating the α3 and α5 chains for biological activities. Incubation of mouse macrophages with the laminin α5 peptide AQARSAASKVKVSMKF resulted in marked increase in matrix metalloproteinase (MMP)-9 mRNA and gelatinolytic activity in the conditioned media, whereas the corresponding α3 peptide QQARDAANKVAIPMRF had no effect. AQARSAASKVKVSMKF also induced expression of MMP-14, while MMP-2, MMP-3, MMP-7, MMP-12, and MMP-13 were not induced by this peptide. Deletion analyses indicated that a minimal sequence of ASKVKVSMKF was sufficient for increasing MMP-9 expression. AQARSAASKVKVSMKF was also chemotactic for neutrophils and macrophages in vitro, and induced accumulation of neutrophils and macrophages in lung airspaces in vivo following intranasal instillation into mice. Comparable accumulation occurred in MMP-9-deficient mice, indicating that MMP-9 was not required for AQARSAASKVKVSMKF-induced inflammatory cell emigration in the lung. A scrambled version of the minimal peptide, KAKSFVMVSK, was inactive. These data indicate that laminin α5-derived peptides can induce inflammatory cell chemotaxis and metalloproteinase activity.

Tumstatin regulates the angiogenic and inflammatory potential of airway smooth muscle extracellular matrix

“…It is known that neutrophil proliferation is enhanced by fibrinogen 31 and survival increased by fibronectin and laminin 32. Laminin enhances protease release from neutrophils and neutrophil chemotaxis 33 potentiating inflammatory cell movement. The current study findings suggest tumstatin has the potential to create an anti‐inflammatory microenvironment, which inhibits neutrophils in the airway tissue.…”

Venular basement membranes contain specific matrix protein low expression regions that act as exit points for emigrating neutrophils

“…The mechanisms by which NE may mediate neutrophil transmigration and/or BM remodeling, directly or indirectly, is at present unclear, especially in the light of the broad substrate specifi city of NE (41). It is of course highly probable that NE may have indirect roles in mediating neutrophil transmigration, for example, via activation of other leukocyte proteases such as MMP-9 (17) or generation of chemotactic fragments by selective cleavage of BM constituents (42)(43)(44) or cellular receptors. However, NE may also play a direct role in mediating neutrophil transmigration, possibly via cleavage of BM constituents (17,40).…”

A Chemotactic Peptide from Laminin α5 Functions as a Regulator of Inflammatory Immune Responses via TNFα-mediated Signaling

“…Because laminin ␣5 is widely expressed in fetal and adult tissues, we are characterizing the function of specific domains of the laminin ␣5 chain. We previously reported that the laminin ␣5 peptide, AQARSAASKVKVSMKF, induces matrix metalloproteinase-9 (MMP-9) production and is chemotactic for leukocytes in vitro and in vivo (8). Furthermore, our data indicated that AQARSAASKVKVSMKF is cryptic in the intact laminin-10 molecule.…”

“…Although the role of ECM in affecting inflammatory cell functions has been examined, the predominant focus has been the effect of ECM components on adhesion, migration (5)(6)(7)(8)(9), and proteinase production (5)(6)(7)(8)(9)(10). Little is known about the effects of ECM components on cytokine production.…”