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Pro-inflammatory cytokine blockade attenuates myeloid expansion in a murine model of rheumatoid arthritis.

ABSTRACT: Rheumatoid arthritis (RA) is a debilitating autoimmune disease characterized by chronic inflammation and progressive destruction of joint tissue. It is also characterized by aberrant blood phenotypes including anemia and suppressed lymphopoiesis that contribute to morbidity in RA patients. However, the impact of RA on hematopoietic stem cells (HSC) has not been fully elucidated. Using a collagen-induced mouse model of human RA, we identified systemic inflammation 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 context of chronic autoimmune arthritis.

SUBMITTER: Hernandez G

PROVIDER: S-EPMC7049366 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Pro-inflammatory cytokine blockade attenuates myeloid expansion in a murine model of rheumatoid arthritis.

Hernandez Giovanny G Mills Taylor S TS Rabe Jennifer L JL Chavez James S JS Kuldanek Susan S Kirkpatrick Gregory G Noetzli Leila L Jubair Widian K WK Zanche Michelle M Myers Jason R JR Stevens Brett M BM Fleenor Courtney J CJ Adane Biniam B Dinarello Charles A CA Ashton John J Jordan Craig T CT Di Paola Jorge J Hagman James R JR Holers V Michael VM Kuhn Kristine A KA Pietras Eric M EM

Haematologica 20190517 3

Rheumatoid arthritis (RA) is a debilitating autoimmune disease characterized by chronic inflammation and progressive destruction of joint tissue. It is also characterized by aberrant blood phenotypes including anemia and suppressed lymphopoiesis that contribute to morbidity in RA patients. However, the impact of RA on hematopoietic stem cells (HSC) has not been fully elucidated. Using a collagen-induced mouse model of human RA, we identified systemic inflammation and myeloid overproduction assoc ...[more]

PMID: 31101752

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Project description:Breast cancer survivors receiving chemotherapy often report increased anxiety and depression. However, the mechanism underlying chemotherapy-induced changes in affect remains unknown. We hypothesized that chemotherapy increases cytokine production, in turn altering exploratory and depressive-like behavior. To test this hypothesis, female Balb/C mice received two injections, separated by two weeks, of vehicle (0.9% saline) or a chemotherapeutic cocktail [9 mg/kg doxorubicin (A) and 90 mg/kg cyclophosphamide (C)]. Peripheral and central cytokine concentrations were increased one and seven days, respectively, after AC. Because of the beneficial effects of social enrichment on several diseases with inflammatory components, we examined whether social enrichment could attenuate the increase in peripheral and central cytokine production following chemotherapy administration. Socially isolated mice receiving AC therapy demonstrated increased depressive-like and exploratory behaviors with a concurrent increase in hippocampal IL-6. Whereas, group housing attenuated AC-induced IL-6 and depressive-like behavior. Next, we sought to determine whether central oxytocin may contribute to the protective effects of social housing after AC administration. Intracerebroventricular administration of oxytocin to socially isolated mice recapitulated the protective effects of social enrichment; specifically, oxytocin ameliorated the AC-induced effects on IL-6 and depressive-like behavior. Furthermore, administration of an oxytocin antagonist to group housed mice recapitulated the responses of socially isolated mice; specifically, AC increased depressive-like behavior and central IL-6. These data suggest a possible neuroprotective role for oxytocin following chemotherapy, via modulation of IL-6. This study adds to the growing literature detailing the negative behavioral effects of chemotherapy and provides further evidence that social enrichment may be beneficial to health.

Dataset Information

Pro-inflammatory cytokine blockade attenuates myeloid expansion in a murine model of rheumatoid arthritis.

Publications

Pro-inflammatory cytokine blockade attenuates myeloid expansion in a murine model of rheumatoid arthritis.

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