| First Author | Artz A | Year | 2016 |
| Journal | Blood | Volume | 128 |
| Issue | 4 | Pages | 529-41 |
| PubMed ID | 27235139 | Mgi Jnum | J:236115 |
| Mgi Id | MGI:5804736 | Doi | 10.1182/blood-2016-01-696617 |
| Citation | Artz A, et al. (2016) GDF-15 inhibits integrin activation and mouse neutrophil recruitment through the ALK-5/TGF-betaRII heterodimer. Blood 128(4):529-41 |
| abstractText | Growth differentiation factor 15 (GDF-15) is the first cytokine known to counteract chemokine-induced activation of leukocyte integrins. We showed recently that this activity dampens neutrophil recruitment into inflamed tissue and is required for survival of myocardial infarction in mice. The receptor responsible for this GDF-15-triggered anti-inflammatory mechanism on myeloid cells is not known. Here, we identify this receptor as transforming growth factor beta receptor I (TGF-betaRI) (activin receptor-like kinase 5 [ALK-5]) and TGF-beta receptor II (TGF-betaRII). We show that interference with these receptors by small-molecule inhibitors, antibodies, or small interfering RNA, blocked the GDF-15 effect on leukocyte integrin activation. Likewise, gene inactivation of each of the 2 receptors in neutrophils isolated from conditional gene-deficient mice abolished the inhibitory effect of GDF-15 on CXCL1-induced beta2-integrin activation and neutrophil diapedesis. Rapid neutrophil arrest induced by CXCL1 in vivo was inhibited by GDF-15 in an ALK-5 and TGF-betaRII dependent way. As for GDF-15 gene-deficient mice, we found that extravasation of neutrophils deficient for ALK-5 or TGF-betaRII was strongly increased in the interleukin-1beta inflamed cremaster. The inhibitory effects of GDF-15 on neutrophil integrin activation and in vivo neutrophil arrest were also found for TGF-beta1. Mechanistically, GDF-15 and TGF-beta1 interfered with integrin activation by inhibiting the activation of Ras-related protein 1 (Rap-1), an effect that depended on CalDAG- guanine nucleotide exchange factor 1 (GEF1) and cell division control protein 42 homolog. We conclude that both GDF-15 and TGF-beta1 counteract chemokine-induced integrin activation on neutrophils via the ALK-5/TGF-betaRII heterodimer. This represents a novel, rapid anti-inflammatory activity of the 2 TGF-beta receptors and of TGF-beta1. |
