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

Karla C Fischer,Anissa M Jabbour,James E Vince,Sheila Dias,Carmel P Daunt,Cédric S Tremblay

doi:10.1038/s41419-020-03298-9

Abstract

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 Rosa26Cre-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.

Highlights

Cytokine receptor signalling is essential for the survival, proliferation and differentiation of haematopoietic stem cells (HSCs) and their progeny
To determine whether aberrant increases in proinflammatory cytokines could be the underlying cause of the intestinal inflammation in mice whose haematopoietic cells had been deleted for IKK2, serum concentrations of interleukin-1 beta (IL-1β), IL-6 and TNFα were measured by enzyme-linked immunosorbent assay (ELISA) at the experimental endpoint
Our findings demonstrate that IKK2 loss, but not loss of IKK1, in adult haematopoietic cells, results in severe neutrophilia, normocytic anaemia and thrombocytosis in peripheral blood, reflecting a skewed lineage commitment, promoting myeloid over erythroid cell fate

Summary

Introduction

Cytokine receptor signalling is essential for the survival, proliferation and differentiation of haematopoietic stem cells (HSCs) and their progeny. Cytokines control the development of haematopoietic progenitors into cells of the myeloid, lymphoid and erythroid lineages by stimulating cell proliferation and differentiation, as well as by inhibiting apoptotic cell death[1,2,3]. The signalling pathways leading to activation of the IKK complex following ligation of the members of the Tumour. Lymphotoxin-β (LT-β)[19], Bcell activating factor (BAFF) and CD40L20–22 trigger activation of IKK1 and non-canonical NF-κB signalling. Inflammatory cytokines, such as tumour necrosis factor (TNF) and interleukin-1β (IL-1β), as well as certain mitogens or bacterial lipopolysaccharide activate IKK2 and canonical NF-κB signalling[23]

Methods

Results

Conclusion