CXCL12 activation of CXCR4 regulates mucosal host defense through stimulation of epithelial cell migration and promotion of intestinal barrier integrity

2005 ◽  
Vol 288 (2) ◽  
pp. G316-G326 ◽  
Author(s):  
Jennifer M. Smith ◽  
Priscilla A. Johanesen ◽  
Michael K. Wendt ◽  
David G. Binion ◽  
Michael B. Dwinell
Keyword(s):  
Wound Healing ◽  
Cell Migration ◽  
Epithelial Cell ◽  
Host Defense ◽  
Intestinal Epithelial Cell ◽  
Mucosal Barrier ◽  
Intestinal Epithelial ◽  
Barrier Integrity ◽  
Epithelial Migration ◽  
Epithelial Cell Migration

Intestinal epithelial cell migration plays a key role in gastrointestinal mucosal barrier formation, enterocyte development, differentiation, turnover, wound healing, and adenocarcinoma metastasis. Chemokines, through engagement of their corresponding receptors, are potent mediators of directed cell migration and are critical in the establishment and regulation of innate and adaptive immune responses. The aim of this study was to define the role for the chemokine CXCL12 and its sole cognate receptor CXCR4 in regulating intestinal epithelial cell migration and to determine its impact on barrier integrity. CXCL12 stimulated the dose-dependent chemotactic migration of human T84 colonic epithelial cells. Epithelial cell migration was inhibited by CXCR4 neutralizing antibody, pertussis toxin, LY-294002, and PD-98059, thereby implicating Gαi, phosphatidylinositol 3-kinase (PI3-kinase), and the ERK1/2 MAP kinase pathways in CXCR4-specific signaling. CXCL12 was also shown to increase barrier integrity, as defined by transepithelial resistance and paracellular flux across differentiating T84 monolayers. To determine whether CXCL12 regulated epithelial restitution, we used the normal nontransformed intestinal epithelial cell-6 (IEC-6) wound healing model. By using RT-PCR, immunoblot analysis, and immunofluorescence microscopy, we first showed expression of both CXCR4 and its ligand by IEC-6 cells. We then demonstrated that CXCL12 activated comparable signaling mechanisms to stimulate epithelial migration in the absence of proliferation in wounded IEC-6 monolayers. Taken together, these data indicate that CXCL12 signaling via CXCR4 directs intestinal epithelial cell migration, barrier maturation, and restitution, consistent with an important mechanistic role for these molecules in mucosal barrier integrity and innate host defense.

scholarly journals Resolvin E1 is a pro-repair molecule that promotes intestinal epithelial wound healing

2020 ◽  
Vol 117 (17) ◽  
pp. 9477-9482 ◽  
Author(s):  
Miguel Quiros ◽  
Darius Feier ◽  
Dorothee Birkl ◽  
Rachit Agarwal ◽  
Dennis W. Zhou ◽  
...  
Keyword(s):  
Wound Healing ◽  
Cell Migration ◽  
Epithelial Cell ◽  
Wound Repair ◽  
Intestinal Epithelial Cell ◽  
Intestinal Inflammation ◽  
Small Gtpase ◽  
Intestinal Epithelial ◽  
Epithelial Cell Migration ◽  
Cell Migration And Proliferation

Resolution of intestinal inflammation and wound repair are active processes that mediate epithelial healing at mucosal surfaces. Lipid molecules referred to as specialized proresolving mediators (SPMs) play an important role in the restorative response. Resolvin E1 (RvE1), a SPM derived from omega-3 fatty acids, has been reported to dampen intestinal inflammation by promoting anti-inflammatory responses including increased neutrophil spherocytosis and macrophage production of IL-10. Despite these observations, a role for RvE1 in regulating intestinal epithelial cell migration and proliferation during mucosal wound repair has not been explored. Using an endoscopic biopsy-based wound healing model, we report that RvE1 is locally produced in response to intestinal mucosal injury. Exposure of intestinal epithelial cells to RvE1 promoted wound repair by increasing cellular proliferation and migration through activation of signaling pathways including CREB, mTOR, and Src-FAK. Additionally, RvE1-triggered activation of the small GTPase Rac1 led to increased intracellular reactive oxygen species (ROS) production, cell–matrix adhesion, and cellular protrusions at the leading edge of migrating cells. Furthermore, in situ administration of RvE1-encapsulated synthetic targeted polymeric nanoparticles into intestinal wounds promoted mucosal repair. Together, these findings demonstrate that RvE1 functions as a prorepair lipid mediator by increasing intestinal epithelial cell migration and proliferation, and highlight potential therapeutic applications for this SPM to promote mucosal healing in the intestine.

Epidermal growth factor stimulates Rac activation through Src and phosphatidylinositol 3-kinase to promote colonic epithelial cell migration

2008 ◽  
Vol 294 (1) ◽  
pp. G276-G285 ◽  
Author(s):  
Rebecca S. Dise ◽  
Mark R. Frey ◽  
Robert H. Whitehead ◽  
D. Brent Polk
Keyword(s):  
Wound Healing ◽  
Cell Migration ◽  
Epithelial Cell ◽  
Intestinal Epithelial Cell ◽  
Wound Closure ◽  
Intestinal Epithelial ◽  
Phosphatidylinositol 3 Kinase ◽  
Epithelial Cell Migration ◽  
Wound Margin ◽  
Epidermal Growth

Regulated intestinal epithelial cell migration plays a key role in wound healing and maintenance of a healthy gastrointestinal tract. Epidermal growth factor (EGF) stimulates cell migration and wound closure in intestinal epithelial cells through incompletely understood mechanisms. In this study we investigated the role of the small GTPase Rac in EGF-induced cell migration using an in vitro wound-healing assay. In mouse colonic epithelial (MCE) cell lines, EGF-stimulated wound closure was accompanied by a doubling of the number of cells containing lamellipodial extensions at the wound margin, increased Rac membrane translocation in cells at the wound margin, and rapid Rac activation. Either Rac1 small interfering (si)RNA or a Rac1 inhibitor completely blocked EGF-stimulated wound closure. Whereas EGF failed to activate Rac in colon cells from EGF receptor (EGFR) knockout mice, stable expression of wild-type EGFR restored EGF-stimulated Rac activation and migration. Pharmacological inhibition of either phosphatidylinositol 3-kinase (PI3K) or Src family kinases reduced EGF-stimulated Rac activation. Cotreatment of cells with both inhibitors completely blocked EGF-stimulated Rac activation and localization to the leading edge of cells and lamellipodial extension. Our results present a novel mechanism by which the PI3K and Src signaling cascades cooperate to activate Rac and promote intestinal epithelial cell migration downstream of EGFR.

scholarly journals Role of K+ channel expression in polyamine-dependent intestinal epithelial cell migration

2000 ◽  
Vol 278 (2) ◽  
pp. C303-C314 ◽  
Author(s):  
Jian-Ying Wang ◽  
Jian Wang ◽  
Vera A. Golovina ◽  
Li Li ◽  
Oleksandr Platoshyn ◽  
...  
Keyword(s):  
Cell Migration ◽  
Epithelial Cell ◽  
Driving Force ◽  
Intestinal Epithelial Cell ◽  
Delayed Rectifier ◽  
Intestinal Epithelial ◽  
Voltage Gated ◽  
Epithelial Cell Migration ◽  
Channel Expression ◽  
Exogenous Spermidine

Polyamines are essential for cell migration during early mucosal restitution after wounding in the gastrointestinal tract. Activity of voltage-gated K+ channels (Kv) controls membrane potential ( E m) that regulates cytoplasmic free Ca2+ concentration ([Ca2+]cyt) by governing the driving force for Ca2+ influx. This study determined whether polyamines are required for the stimulation of cell migration by altering K+ channel gene expression, E m, and [Ca2+]cyt in intestinal epithelial cells (IEC-6). The specific inhibitor of polyamine synthesis, α-difluoromethylornithine (DFMO, 5 mM), depleted cellular polyamines (putrescine, spermidine, and spermine), selectively inhibited Kv1.1 channel (a delayed-rectifier Kv channel) expression, and resulted in membrane depolarization. Because IEC-6 cells did not express voltage-gated Ca2+ channels, the depolarized E m in DFMO-treated cells decreased [Ca2+]cyt as a result of reduced driving force for Ca2+ influx through capacitative Ca2+ entry. Migration was reduced by 80% in the polyamine-deficient cells. Exogenous spermidine not only reversed the effects of DFMO on Kv1.1 channel expression, E m, and [Ca2+]cyt but also restored cell migration to normal. Removal of extracellular Ca2+ or blockade of Kv channels (by 4-aminopyridine, 1–5 mM) significantly inhibited normal cell migration and prevented the restoration of cell migration by exogenous spermidine in polyamine-deficient cells. These results suggest that polyamine-dependent intestinal epithelial cell migration may be due partially to an increase of Kv1.1 channel expression. The subsequent membrane hyperpolarization raises [Ca2+]cyt by increasing the driving force (the electrochemical gradient) for Ca2+ influx and thus stimulates cell migration.

scholarly journals Ursodeoxycholic acid protects against intestinal barrier breakdown by promoting enterocyte migration via EGFR- and COX-2-dependent mechanisms

2018 ◽  
Vol 315 (2) ◽  
pp. G259-G271 ◽  
Author(s):  
Jamie M. Golden ◽  
Oswaldo H. Escobar ◽  
Michelle V. L. Nguyen ◽  
Michael U. Mallicote ◽  
Patil Kavarian ◽  
...  
Keyword(s):  
Cell Migration ◽  
Epithelial Cell ◽  
Ursodeoxycholic Acid ◽  
Intestinal Epithelial Cell ◽  
Growth Factor Receptor ◽  
Intestinal Barrier ◽  
Intestinal Epithelial ◽  
Epithelial Cell Migration ◽  
Cox 2

The intestinal barrier is often disrupted in disease states, and intestinal barrier failure leads to sepsis. Ursodeoxycholic acid (UDCA) is a bile acid that may protect the intestinal barrier. We hypothesized that UDCA would protect the intestinal epithelium in injury models. To test this hypothesis, we utilized an in vitro wound-healing assay and a mouse model of intestinal barrier injury. We found that UDCA stimulates intestinal epithelial cell migration in vitro, and this migration was blocked by inhibition of cyclooxygenase 2 (COX-2), epidermal growth factor receptor (EGFR), or ERK. Furthermore, UDCA stimulated both COX-2 induction and EGFR phosphorylation. In vivo UDCA protected the intestinal barrier from LPS-induced injury as measured by FITC dextran leakage into the serum. Using 5-bromo-2′-deoxyuridine and 5-ethynyl-2′-deoxyuridine injections, we found that UDCA stimulated intestinal epithelial cell migration in these animals. These effects were blocked with either administration of Rofecoxib, a COX-2 inhibitor, or in EGFR-dominant negative Velvet mice, wherein UDCA had no effect on LPS-induced injury. Finally, we found increased COX-2 and phosphorylated ERK levels in LPS animals also treated with UDCA. Taken together, these data suggest that UDCA can stimulate intestinal epithelial cell migration and protect against acute intestinal injury via an EGFR- and COX-2-dependent mechanism. UDCA may be an effective treatment to prevent the early onset of gut-origin sepsis. NEW & NOTEWORTHY In this study, we show that the secondary bile acid ursodeoxycholic acid stimulates intestinal epithelial cell migration after cellular injury and also protects the intestinal barrier in an acute rodent injury model, neither of which has been previously reported. These effects are dependent on epidermal growth factor receptor activation and downstream cyclooxygenase 2 upregulation in the small intestine. This provides a potential treatment for acute, gut-origin sepsis as seen in diseases such as necrotizing enterocolitis.

K+ channels regulate polyamine-dependent intestinal epithelial cell migration through Ca2+-rhoa signaling pathway

2000 ◽  
Vol 118 (4) ◽  
pp. A675 ◽  
Author(s):  
Rao N. Jaladanki ◽  
Li Li ◽  
Eric D. Strauch ◽  
Vera A. Golovina ◽  
Jason X-J Yuan ◽  
...  
Keyword(s):  
Cell Migration ◽  
Epithelial Cell ◽  
Signaling Pathway ◽  
Intestinal Epithelial Cell ◽  
Intestinal Epithelial ◽  
K Channels ◽  
Epithelial Cell Migration ◽  
Rhoa Signaling
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