Page 71 - Haematologica March 2020

Hematopoiesis
Pro-inflammatory cytokine blockade attenuates myeloid expansion in a murine model of rheumatoid arthritis
Ferrata Storti Foundation
Haematologica 2020 Volume 105(3):585-597
Giovanny Hernandez,1 Taylor S. Mills,1 Jennifer L. Rabe,1 James S. Chavez,1 Susan Kuldanek,1 Gregory Kirkpatrick,2 Leila Noetzli,2 Widian K. Jubair,3 Michelle Zanche,4 Jason R. Myers,4 Brett M. Stevens,1 Courtney J. Fleenor,5,6 Biniam Adane,1 Charles A. Dinarello,7 John Ashton,4 Craig T. Jordan,1 Jorge Di Paola,2 James R. Hagman,5,6 V. Michael Holers,3 Kristine A. Kuhn3 and Eric M. Pietras1,6
1Division of Hematology, University of Colorado Anschutz Medical Campus, Aurora, CO; 2Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO; 3Division of Rheumatology, University of Colorado Anschutz Medical Campus, Aurora, CO; 4Genomics Research Center, University of Rochester, Rochester, NY; 5Department of Biomedical Research, National Jewish Health, Denver, CO; 6Department of Immunology & Microbiology, University of Colorado Anschutz Medical Campus, Aurora, CO and 7Division of Infectious Disease, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
ABSTRACT
Rheumatoid arthritis (RA) is a debilitating autoimmune disease characterized by chronic inflammation and progressive destruc- tion of joint tissue. It is also characterized by aberrant blood phe- notypes including anemia and suppressed lymphopoiesis that contribute to morbidity in RA patients. However, the impact of RA on hematopoi- etic stem cells (HSC) has not been fully elucidated. Using a collagen- induced mouse model of human RA, we identified systemic inflamma- tion and myeloid overproduction associated with activation of a myeloid differentiation gene program in HSC. Surprisingly, despite ongoing inflammation, HSC from arthritic mice remain in a quiescent state associated with activation of a proliferation arrest gene program. Strikingly, we found that inflammatory cytokine blockade using the interleukin-1 receptor antagonist anakinra led to an attenuation of inflammatory arthritis and myeloid expansion in the bone marrow of arthritic mice. In addition, anakinra reduced expression of inflammation- driven myeloid lineage and proliferation arrest gene programs in HSC of arthritic mice. Altogether, our findings show that inflammatory cytokine blockade can contribute to normalization of hematopoiesis in the con- text of chronic autoimmune arthritis.
Introduction
Rheumatoid arthritis (RA) is a chronic, systemic inflammatory autoimmune dis- ease affecting up to 1% of the population.1 RA is associated with significant mor- bidity and mortality, and substantial healthcare-related costs.2 While the pathogen- esis of RA is most often associated with breaking of central tolerance and activa- tion of autoimmune T and B lymphocytes, all types of blood cells contribute to the RA disease process. Platelets and myeloid cells, such as neutrophils and macrophages, have been shown to infiltrate the joint synovia, damaging tissue and presenting antigens that initiate autoimmunity.3 RA is also associated with co-mor- bid hematologic manifestations including chronic anemia, impaired production of naïve T cells, autoimmune cytopenias and leukocytosis during disease ‘flares’.4-7 In addition, RA is associated with elevated levels of pro-inflammatory cytokines including interleukin-1 (IL-1), tumor necrosis factor (TNF) and interferon (IFN)-γ.4 Therapeutic blockade of these factors has been used with success to alleviate the symptoms of inflammatory arthritis in patients, underscoring the importance of pro-inflammatory cytokines in the pathogenesis of RA.5
Correspondence:
ERIC M. PIETRAS eric.pietras@CUAnschutz.edu
Received: May 6, 2018. Accepted: April 17, 2019. Pre-published: May 30, 2019.
doi:10.3324/haematol.2018.197210
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/105/3/585
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haematologica | 2020; 105(3)
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