Cell adhesion protein fibulin‐7 and its C‐terminal fragment negatively regulate monocyte and macrophage migration and functionsin vitroandin vivo

Abstract

Fibulin-7 (Fbln7) has been identified as the latest member of the fibulin family of secreted glycoproteins in developing teeth, functioning as a cell adhesion molecule and interacting with other matrix proteins, receptors, and growth factors. More recently, we have shown that the C-terminal Fbln7 fragment (Fbln7-C) has antiangiogenic activity in vitro. Fbln7 is also expressed in immune-privileged tissues, such as eye and placenta, but its functional significance is unknown. In the current study, we show that human monocytes adhere to both full-length Fbln7 (Fbln7-FL) and Fbln7-C, in part, via integrins αβ and αβ. Morphologic studies and surface expression analyses of CD14, mannose receptor (CD206), major histocompatibility complex II, and CD11b receptors revealed that both Fbln7-FL and Fbln7-C inhibit M-CSF-induced monocyte differentiation. Fbln7-C had significantly greater negative effects on cell spreading and stress fiber formation, including the production of IL-6 and metalloproteinase-1/-9 compared with Fbln7-FL. Furthermore, in an LPS-induced systemic inflammation model, Fbln7-C and Fbln7-FL reduced the infiltration of immune cells, such as neutrophils and macrophages, to the inflamed peritoneum. Thus, these results suggest that Fbln7 and Fbln7-C could modulate the activity of immune cells and have therapeutic potential for inflammatory diseases.-Sarangi, P. P., Chakraborty, P., Dash, S. P., Ikeuchi, T., de Vega, S., Ambatipudi, K., Wahl, L., Yamada, Y. Cell adhesion protein fibulin-7 and its C-terminal fragment negatively regulate monocyte and macrophage migration and functions in vitro and in vivo.

Extracellular Interactions between Fibulins and Transforming Growth Factor (TGF)-β in Physiological and Pathological Conditions

“…Fibulin-7 also plays a role as an angiogenesis inhibitor by promoting endothelial cell adhesion and inhibiting endothelial tube formation via β1-integrin and heparan sulfate receptors [ 126 ]. A recent study by Sarangi et al demonstrated that fibulin-7 and its C-terminal fragment negatively regulate monocyte and macrophage migration, differentiation, and cytokine production, suggesting their potential immunomodulatory role in treating inflammatory diseases [ 127 ].…”

A C‐terminal fragment of adhesion protein fibulin‐7 inhibits growth of murine breast tumor by regulating macrophage reprogramming

“…Since Fbln7‐C binds to surface integrin receptors, the effect may be associated with the expression dynamics of macrophage surface integrins. We have previously demonstrated that Fbln7‐C could compete with fibronectin in binding with monocyte integrin and could inhibit monocyte binding and spreading on fibronectin [15]. Thus, our data indicate that Fbln7‐C may be able to balance the tumor‐induced immunosuppressive programming by providing resistance to tumor environment‐mediated reprogramming of TAM.…”

“…We previously showed that Fbln7‐C could regulate the differentiation and inflammatory functions of monocytes and macrophages both in vitro and in vivo [15]. Therefore, we hypothesized that Fbln7‐C could also modulate the signals that drive macrophage polarization and reprogramming in different microenvironments, including cancers.…”

“…It is known that signaling via integrin could modulate cellular functions via STAT and ERK pathways [27]. Previous studies have shown that Fbln7‐C could bind to integrin β1 on HUVEC cells and monocytes and modulate their functions [13,15]. Similarly, multiple reports have emphasized the role of adhesion receptors, such as integrin in cancer cell survival and proliferation [28].…”

Fibulin‐7 is overexpressed in glioblastomas and modulates glioblastoma neovascularization through interaction with angiopoietin‐1

“…14,15 Overexpression of Fbln3 and Fbln4 has been reported in GBM, 16,17 but the Human Protein Atlas Database on human cancers (https://www.proteinatlas.org) has indicated that Fbln7 is also upregulated in several other cancers, with the highest expression in gliomas. Fbln7, which was identified as an ECM molecule in developing teeth, 18 is expressed in both antiangiogenic tissue cartilage and angiogenesis-related and immunoprivileged tissues such as the eye and placenta, 18,19 and the C-terminal fragment of Fbln7 exerts antiangiogenic activity. 20,21 Matricellular proteins such as Fbln3 and tenascin-C are reported to promote angiogenesis in GBM by modulating the proangiogenic and antiangiogenetic signaling.…”