Prostaglandin E 2 modulates the functional responsiveness of human monocytes to chemokines

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The control of dendritic cell (DC) migration is pivotal for the initiation of cellular immune responses. In this study, we demonstrate that the migration of human monocyte-derived (Mo)DCs as well as of ex vivo peripheral blood DCs toward CCL21, CXCL12, and C5a is stringently dependent on the presence of the proinflammatory mediator PGE2, although DCs expressed CXCR4 and C5aR on their surface and DC maturation was accompanied by CCR7 up-regulation independently of PGE2. The necessity of exogenous PGE2 for DC migration is not due to the suppression of PGE2 synthesis by IL-4, which is used for MoDC differentiation, because maturation-induced endogenous production of PGE2 cannot promote DC migration. Surprisingly, PGE2 was absolutely required at early time points of maturation to enable MoDC chemotaxis, whereas PGE2 addition during terminal maturation events was ineffective. In contrast to mouse DCs, which exclusively rely on EP4 receptor triggering for migration, human MoDCs require a signal mediated by EP2 or EP4 either alone or in combination. Our results provide clear evidence that PGE2 is a general and mandatory factor for the development of a migratory phenotype of human MoDCs as well as for peripheral blood myeloid DCs.

Section: Discussionmentioning

confidence: 99%

Prostaglandin E2 Is Generally Required for Human Dendritic Cell Migration and Exerts Its Effect via EP2 and EP4 Receptors

Legler

Krause

Scandella

et al. 2006

189

202

“…F-actin content was determined with FITC-coupled phalloidin (P5282; Sigma-Aldrich) in human CCR6 + or CXCR3 + cells following chemokine receptor triggering as previously described (47). Briefly, stimulations were performed with 100 nM CCL20 or 100 nM CXCL10, respectively.…”

Section: Actin Polymerization Assaymentioning

confidence: 99%

Impairment of CCR6+ and CXCR3+ Th Cell Migration in HIV-1 Infection Is Rescued by Modulating Actin Polymerization

Cecchinato

Bernasconi

Speck

et al. 2017

Self Cite

CD4+ T cell repopulation of the gut is rarely achieved in HIV-1–infected individuals who are receiving clinically effective antiretroviral therapy. Alterations in the integrity of the mucosal barrier have been indicated as a cause for chronic immune activation and disease progression. In this study, we present evidence that persistent immune activation causes impairment of lymphocytes to respond to chemotactic stimuli, thus preventing their trafficking from the blood stream to peripheral organs. CCR6+ and CXCR3+ Th cells accumulate in the blood of aviremic HIV-1–infected patients on long-term antiretroviral therapy, and their frequency in the circulation positively correlates to levels of soluble CD14 in plasma, a marker of chronic immune activation. Th cells show an impaired response to chemotactic stimuli both in humans and in the pathogenic model of SIV infection, and this defect is due to hyperactivation of cofilin and inefficient actin polymerization. Taking advantage of a murine model of chronic immune activation, we demonstrate that cytoskeleton remodeling, induced by okadaic acid, restores lymphocyte migration in response to chemokines, both in vitro and in vivo. This study calls for novel pharmacological approaches in those pathological conditions characterized by persistent immune activation and loss of trafficking of T cell subsets to niches that sustain their maturation and activities.

“…PGs can regulate chemokine and chemokine receptor expression, although the role of PGs in cell migration might depend on the cell type analyzed. PGE 2 is an inducer of CCR7 expression and DC migration in response to CCL19 and CCL21 (31), whereas it downregulates CCR5 (26) in macrophages. Moreover, control of migration of immune cells by PGs is involved in the progression of some diseases.…”

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confidence: 99%

“…PGD 2 is a chemotactic agent for DCs and Th2 cells, whereas PGF 2a was shown to induce neutrophil migration (23,24). PGE 2 enhances hematopoietic cell homing and modulates monocyte response to chemokines (25,26). PGE 2 can also favor migration of DCs to lymph nodes, likely by inducing MMP9 expression (27)(28)(29).…”

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confidence: 99%

Cyclooxygenase-2 Deficiency in Macrophages Leads to Defective p110γ PI3K Signaling and Impairs Cell Adhesion and Migration

Díaz-Muñoz

Osma-García

Íñiguez

et al. 2013

Cyclooxygenase (Cox)-2 dependent PGs modulate several functions in many pathophysiological processes, including migration of immune cells. In this study, we addressed the role of Cox-2 in macrophage migration by using in vivo and in vitro models. Upon thioglycolate challenge, CD11b+ F4/80+ macrophages showed a diminished ability to migrate to the peritoneal cavity in cox-2−/− mice. In vivo migration of cox-2−/− macrophages from the peritoneal cavity to lymph nodes, as well as cell adhesion to the mesothelium, was reduced in response to LPS. In vitro migration of cox-2−/− macrophages toward MCP-1, RANTES, MIP-1α, or MIP-1β, as well as cell adhesion to ICAM-1 or fibronectin, was impaired. Defects in cell migration were not due to changes in chemokine receptor expression. Remarkably, cox-2−/− macrophages showed a deficiency in focal adhesion formation, with reduced phosphorylation of paxillin (Tyr188). Interestingly, expression of the p110γ catalytic subunit of PI3K was severely reduced in the absence of Cox-2, leading to defective Akt phosphorylation, as well as cdc42 and Rac-1 activation. Our results indicate that the paxillin/p110γ-PI3K/Cdc42/Rac1 axis is defective in cox-2−/− macrophages, which results in impaired cell adhesion and migration.