Inhibitor of NF-κB kinases α and β are both essential for high mobility group box 1-mediated chemotaxis

Marianna Penzo, Raffaella Molteni, Tomomi Suda, Sylvia Samaniego, Angela Raucci, David M. Habiel, Frederick Miller, Hui Ping Jiang, Jun Li, Ruggero Pardi, Roberta Palumbo, Eleonora Olivotto, Richard R. Kew, Marco E. Bianchi, Kenneth B. Marcu

Research output: Contribution to journalArticlepeer-review

Abstract

Inhibitor of NF-κB kinases β (IKKβ) and α (IKKα) activate distinct NF-κB signaling modules. The IKKβ/canonical NF-κB pathway rapidly responds to stress-like conditions, whereas the IKKα/noncanonical pathway controls adaptive immunity. Moreover, IKKα can attenuate IKKβ-initiated inflammatory responses. High mobility group box 1 (HMGB1), a chromatin protein, is an extracellular signal of tissue damage-attracting cells in inflammation, tissue regeneration, and scar formation. We show that IKKα and IKKβ are each critically important for HMGB1-elicited chemotaxis of fibroblasts, macrophages, and neutrophils in vitro and neutrophils in vivo. By time-lapse microscopy we dissected different parameters of the HMGB1 migration response and found that IKKα and IKKβ are each essential to polarize cells toward HMGB1 and that each kinase also differentially affects cellular velocity in a time-dependent manner. In addition, HMGB1 modestly induces noncanonical IKKα-dependent p52 nuclear translocation and p52/RelB target gene expression. Akin to IKKα and IKKβ, p52 and RelB are also required for HMGB1 chemotaxis, and p52 is essential for cellular orientation toward an HMGB1 gradient. RAGE, a ubiquitously expressed HMGB1 receptor, is required for HMGB1 chemotaxis. Moreover, IKKβ, but not IKKα, is required for HMGB1 to induce RAGE mRNA, suggesting that RAGE is at least one IKKβ target involved in HMGB1 migration responses, and in accord with these results enforced RAGE expression rescues the HMGB1 migration defect of IKKβ, but not IKKα, null cells. Thus, proinflammatory HMGB1 chemotactic responses mechanistically require the differential collaboration of both IKK-dependent NF-κB signaling pathways.

Original languageEnglish
Pages (from-to)4497-4509
Number of pages13
JournalJournal of Immunology
Volume184
Issue number8
DOIs
Publication statusPublished - Apr 15 2010

ASJC Scopus subject areas

  • Immunology
  • Medicine(all)

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