| CCN1 is a member of the CCN matricellular protein family that consists of 6 structurally related members. CCN1 plays critical roles in cardiovascular development during embryogenesis, and participates in wound healing and pathogenesis of a variety of diseases in adults. Purified CCN1 protein regulates diverse cellular functions including cell adhesion, migration, proliferation, differentiation, survival and apoptosis. Many of these functions can be attributed to the direct interaction of CCN1 with integrin and cell surface heparan sulfate proteoglycans (HSPGs) receptors.;Consistent to its aberrant expression at the injury sites, CCN1 protein, interacting with integrin alphaMbeta2 and HSPG syndecan 4, supports macrophage adhesion, activates NF-kappaB pathways and regulates the expression of a global pro-inflammatory genetic program that involves multiple cytokines, chemokines, and other molecular players in the inflammatory response.;The ligation to receptors alphaMbeta2/alpha 6beta1/HSPGs through the C2 sequence is central for CCN1-mediated inflammatory signaling because mutations within the H2 motif completely abrogate activities dependent on these binding sites.;Employing the DM protein, an alphaMbeta2/alpha 6beta1/HSPGs-binding defective CCN1 mutant, as well as its respective homozygous knock-in CCN1dm/dm mice, we further demonstrate the importance of the receptors for modulating inflammation both in vitro and in vivo, including neutrophils recruitment, and cytokine production by macrophages. Due to the attenuated inflammatory response, Ccn1dm/dm wounds heal considerably faster, accompanied with earlier clearance of apoptotic cells and cytokines in the granulation tissue.;Together, these results reinforce the notion that the ECM microenvironment effectively modulates inflammation process, and highlight CCN1 as a novel player in regulating the inflammatory response of macrophages and neutrophils through integrin and HSPGs receptors. |
