CCN1: a novel inflammation-regulated biphasic immune cell migration modulator

Abstract

In this study, we performed a comprehensive analysis of the effect of CCN1 on the migration of human immune cells. The molecule CCN1, produced by fibroblasts and endothelial cells, is considered as an important matrix protein promoting tissue repair and immune cell adhesion by binding various integrins. We recently reported that CCN1 therapy is able to suppress acute inflammation in vivo. Here, we show that CCN1 binds to various immune cells including T cells, B cells, NK cells, and monocytes. The addition of CCN1 in vitro enhances both actin polymerization and transwell migration. Prolonged incubation with CCN1, however, results in the inhibition of migration of immune cells by a mechanism that involves downregulation of PI3Kγ, p38, and Akt activation. Furthermore, we observed that immune cells themselves produce constitutively CCN1 and secretion is induced by pro-inflammatory stimuli. In line with this finding, patients suffering from acute inflammation had enhanced serum levels of CCN1. These findings extend the classical concept of CCN1 as a locally produced cell matrix adhesion molecule and suggest that CCN1 plays an important role in regulating immune cell trafficking by attracting and locally immobilizing immune cells.

Denervation protects limbs from inflammatory arthritis via an impact on the microvasculature

“…Angiopoietin-like 4, structurally similar to the angiopoietins, protects vascular integrity in contexts of myocardial infarction and tumor metastasis; Angptl4-KO mice showed altered VEGFR2/VE-cadherin complexes and disrupted endothelial cell adherens junctions (32,33). Cysteine-rich angiogenic inducer 61 (encoding by Cr61), produced by fibroblasts and endothelial cells, is considered an important matrix protein promoting tissue repair and immune cell adhesion by binding various integrins; high expression of this molecule inhibits transmigration of innate and adaptive immune cells (34). Clearly, transcriptome changes in hindpaw endothelial cells support the notion that vascular alterations in the denervated limbs reduce access to arthritogenic cells and molecules.…”

Postoperative Accumulation of Cyr61/CCN1 in Surgical Wound Fluid Precedes Cytokine Activation and is Disparate from Systemic Alterations

“…Similarly, CCN1 levels were substantially higher than reference levels at wound closure and increased throughout the study period. CCN1 is a ubiquitously expressed and secreted protein, and fibroblasts, endothelial cells, smooth and striated muscle cells, and immune cells have been reported to produce and secrete CCN1 in response to environmental stressors, such as coagulation factors, eicosanoids, hormones, hypoxia, and inflammatory cytokines [6,7,36]. All of these factors, which stimulate the aforementioned cell types, may have contributed cumulatively to the increased CCN1 levels in the drained fluid.…”

Thymic epithelial cell expansion through matricellular protein CYR61 boosts progenitor homing and T-cell output

“…S2c). Although CYR61 can promote or inhibit cell migration depending on cell type 19,20 , we observed no chemotactic activity of CYR61 on any thymocyte subset (Fig. 2d).…”

“…47). CYR61 has also been reported to promote the adhesion and transendothelial migration of circulating hematopoietic CD34 þ precursors 16 , as well as the migration of PBMC 20 . However, we did not observe chemotactic activity of CYR61 on developing thymocytes in similar transwell experiments.…”

“…Notably, Cyr61-deficient mice are embryonic lethal because of cardiovascular defects 18 . Depending on the cell type and context, CYR61 can promote the proliferation, survival, migration or senescence of cells 14,[17][18][19][20] . CYR61 is overexpressed in various cancer cells, including cancers of epithelial origin, and can promote their proliferation [21][22][23] .…”