Deletion of IKK2 in haematopoietic cells of adult mice leads to elevated interleukin-6, neutrophilia and fatal gastrointestinal inflammation

• Published in: Cell death & disease Vol. 12; no. 1; p. 28
• Main Authors: Fischer, Karla C., Daunt, Carmel P., Tremblay, Cédric S., Dias, Sheila, Vince, James E., Jabbour, Anissa M.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 04-01-2021; Springer Nature B.V; Nature Publishing Group
• Subjects: 13/100; 13/31; 14/63; 631/250/127/1213; 631/250/232/2059; 631/250/249/2510; 631/532/1542; 631/80/86/2368; 64/60; 82/1; 82/80; 96/21; Animals; Antibodies; Biochemistry; Biomedical and Life Sciences; Catalytic subunits; CD11b antigen; Cell activation; Cell Biology; Cell Culture; Cell Differentiation; Cell proliferation; Cell surface; Cell survival; Clonal deletion; Cytokines; Female; Gastritis - immunology; Gene deletion; Hematopoiesis - immunology; Hematopoietic stem cells; I-kappa B Kinase - immunology; IKK protein; IKK2 protein; Immune response; Immunology; Inflammation; Interleukin 1; Interleukin 6; Interleukin-6 - immunology; Life Sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; Myeloid cells; Neutrophilia; NF-kappa B - immunology; NF-κB protein; Progenitor cells; Recombination; Stem cell transplantation; Stem cells; Stem Cells - cytology; Stem Cells - immunology; Thrombocytosis; Tumor necrosis factor; Tumors
• DOI: 10.1038/s41419-020-03298-9
• EISSN: 2041-4889

The IκB kinase complex, consisting of IKK1, IKK2 and the regulatory subunit NEMO, is required for NF-κB signalling following the activation of several cell surface receptors, such as members of the Tumour Necrosis Factor Receptor superfamily and the Interleukin-1 Receptor. This is critical for haematopoietic cell proliferation, differentiation, survival and immune responses. To determine the role of IKK in the regulation of haematopoiesis, we used the Rosa26
Cre-ERT2
Cre/lox recombination system to achieve targeted, haematopoietic cell-restricted deletion of the genes for IKK1 or IKK2 in vivo. We found that the IKK complex plays a critical role in haematopoietic cell development and function. Deletion of IKK2, but not loss of IKK1, in haematopoietic cells led to an expansion of CD11b/Gr-1-positive myeloid cells (neutrophilia), severe anaemia and thrombocytosis, with reduced numbers of long-term haematopoietic stem cells (LT-HSCs), short-term haematopoietic stem cells (ST-HSCs) and multipotential progenitor cells (MPPs), increased circulating interleukin-6 (IL-6) and severe gastrointestinal inflammation. These findings identify distinct functions for the two IKK catalytic subunits, IKK1 and IKK2, in the haematopoietic system.