Cell migration to CXCL12 requires simultaneous IKK\u3b1 and IKK\u3b2-dependent NF-\u3baB signaling

CXCL12 and its unique receptor CXCR4, is critical for the homing of a variety of cell lineages during both development and tissue repair. CXCL12 is particularly important for the recruitment of hemato/lymphopoietic cells to their target organs. In conjunction with the damage-associated alarmin molecule HMGB1, CXCL12 mediates immune effector and stem/progenitor cell migration towards damaged tissues for subsequent repair. Previously, we showed that cell migration to HMGB1 simultaneously requires both IKK beta and IKK alpha-dependent NF-kappa B activation. IKK beta-mediated activation maintains sufficient expression of HMGB1's receptor RAGE, while IKK alpha-dependent NF-kappa B activation ensures continuous production of CXCL12, which complexes with HMGB1 to engage CXCR4. Here using fibroblasts and primary mature macrophages, we show that IKK beta and IKK alpha are simultaneously essential for cell migration in response to CXCL12 alone. Non-canonical NF-kappa B pathway subunits RelB and p52 are also both essential for cell migration towards CXCL12, suggesting that IKK alpha is required to drive non-canonical NF-kappa B signaling. Flow cytometric analyses of CXCR4 expression show that IKK beta, but not IKK alpha, is required to maintain a critical threshold level of this CXCL12 receptor. Time-lapse video microscopy experiments in primary MEFs reveal that IKK alpha is required both for polarization of cells towards a CXCL12 gradient and to establish a basal level of velocity towards CXCL12. In addition, CXCL12 modestly up-regulates IKK alpha-dependent p52 nuclear translocation and IKK alpha-dependent expression of the CXCL12 gene. On the basis of our collective results we posit that IKK alpha is needed to maintain the basal expression of a critical protein co-factor required for cell migration to CXCL12

TRAIL-Dependent Resolution of Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) is the most common form of interstitial lung disease characterized by the persistence of activated myofibroblasts resulting in excessive deposition of extracellular matrix proteins and profound tissue remodeling. In the present study, the expression of tumor necrosis factor- (TNF-) related apoptosis-inducing ligand (TRAIL) was key to the resolution of bleomycin-induced pulmonary fibrosis. Both in vivo and in vitro studies demonstrated that Gr-1+TRAIL+ bone marrow-derived myeloid cells blocked the activation of lung myofibroblasts. Although soluble TRAIL was increased in plasma from IPF patients, the presence of TRAIL+ myeloid cells was markedly reduced in IPF lung biopsies, and primary lung fibroblasts from this patient group expressed little of the TRAIL receptor-2 (DR5) when compared with appropriate normal samples. IL-13 was a potent inhibitor of DR5 expression in normal fibroblasts. Together, these results identified TRAIL+ myeloid cells as a critical mechanism in the resolution of pulmonary fibrosis, and strategies directed at promoting its function might have therapeutic potential in IPF