Cell migration to CXCL12 requires simultaneous IKK? and IKK?-dependent NF-?B signaling.

ABSTRACT: 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? and IKK?-dependent NF-?B activation. IKK?-mediated activation maintains sufficient expression of HMGB1's receptor RAGE, while IKK?-dependent NF-?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? and IKK? are simultaneously essential for cell migration in response to CXCL12 alone. Non-canonical NF-?B pathway subunits RelB and p52 are also both essential for cell migration towards CXCL12, suggesting that IKK? is required to drive non-canonical NF-?B signaling. Flow cytometric analyses of CXCR4 expression show that IKK?, but not IKK?, is required to maintain a critical threshold level of this CXCL12 receptor. Time-lapse video microscopy experiments in primary MEFs reveal that IKK? 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?-dependent p52 nuclear translocation and IKK?-dependent expression of the CXCL12 gene. On the basis of our collective results we posit that IKK? is needed to maintain the basal expression of a critical protein co-factor required for cell migration to CXCL12.

SUBMITTER: Penzo M 

PROVIDER: S-EPMC4096130 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature