Oxidant signaling mediated by Nox2 in neutrophils promotes regenerative myelopoiesis and tissue recovery following ischemic damage

Milie M. Fang, Pijus K. Barman, Muthusamy Thiruppathi, Rita E. Mirza, Ronald D. McKinney, Jing Deng, John W. Christman, Xiaoping Du, Tohru Fukai, William J. Ennis, Timothy J. Koh, Masuko Ushio-Fukai, Norifumi Urao

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4 Scopus citations

Abstract

Ischemic tissue damage activates hematopoietic stem and progenitor cells (HSPCs) in the bone marrow (BM)-generating myeloid cells, and persistent HSPC activity may drive chronic inflammation and impair tissue recovery. Although increased reactive oxygen species in the BM regulate HSPC functions, their roles in myelopoiesis of activated HSPCs and subsequent tissue recovery during ischemic damage are not well understood. In this paper, we report that deletion of Nox2 NADPH oxidase in mice results in persistent elevations in BM HSPC activity and levels of inflammatory monocytes/macrophages in BM and ischemic tissue in a model of hindlimb ischemia. Ischemic tissue damage induces oxidants in BM such as elevations of hydrogen peroxide and oxidized phospholipids, which activate redox-sensitive Lyn kinase in a Nox2-dependent manner. Moreover, during tissue recovery after ischemic injury, this Nox2-ROS-Lyn kinase axis is induced by Nox2 in neutrophils that home to the BM, which inhibits HSPC activity and inflammatory monocyte generation and promotes tissue regeneration after ischemic damage. Thus, oxidant signaling in the BM mediated by Nox2 in neutrophils regulates myelopoiesis of HSPCs to promote regeneration of damaged tissue.

Original languageEnglish (US)
Pages (from-to)2414-2426
Number of pages13
JournalJournal of Immunology
Volume201
Issue number8
DOIs
StatePublished - Oct 15 2018

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ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Fang, M. M., Barman, P. K., Thiruppathi, M., Mirza, R. E., McKinney, R. D., Deng, J., Christman, J. W., Du, X., Fukai, T., Ennis, W. J., Koh, T. J., Ushio-Fukai, M., & Urao, N. (2018). Oxidant signaling mediated by Nox2 in neutrophils promotes regenerative myelopoiesis and tissue recovery following ischemic damage. Journal of Immunology, 201(8), 2414-2426. https://doi.org/10.4049/jimmunol.1800252