TNFα signaling restores steady-state hematopoiesis in a TNFαKO mouse model of anemia of inflammation
Abstract
Abstract Anemia of inflammation (AI) is the second most common form of anemia and is prevalent in patients with chronic inflammatory states, such as infection, autoimmunity, and cancer. Interleukin 6 (IL-6) is well-known to induce the iron-sequestering hormone hepcidin, which results in iron-restricted anemia. The contributions of other proinflammatory cytokines, such as tumor necrosis factor-α (TNFα) and interferon gamma (IFNγ), are less understood in the pathophysiology of AI. This study investigated the role of TNFα in a mouse model of AI by administering heat-killed Brucella abortus (HKBA) to germ line TNFα knockout (KO) mice. We hypothesized that TNFα possessed an important role in restoring steady-state erythropoiesis after inflammatory insult. TNFαKO injected with HKBA displayed a chronic anemia, with elevated proinflammatory IL12p40 and IFNγ cytokines that did not resolve. However, IFNγKO and TNFαKO/FNγKO double knockout mice showed reduced inflammation and anemia following HKBA administration. Because IFNγKO displayed normal serum TNFα and IL12p40 levels, we hypothesized that the persistent anemia was IFNγ induced and TNFα was necessary for AI cessation. However, treatment with recombinant TNFα (rTNFα) accelerated death, while reducing IFNγ using an anti-IFNγ antibody (Ab) only briefly improved anemia. Only the combination of both the Ab and rTNFα together reversed the hyperinflammatory phenotype, restored erythropoiesis, and prevented death of TNFαKO + HKBA mice. Our data provide compelling evidence for an anti-inflammatory role of TNFα that is necessary for the restoration of erythropoiesis and mitigation of proinflammatory IFNγ action in a mouse model of AI.
Article Details
Authors (17)
Amaliris Guerra
1Division of Hematology, Department of Pediatrics, The Children’s Hospital of Philadelphia, Philadelphia, PA
Vania lo Presti
Ding-Wen Chen
1Division of Hematology, Department of Pediatrics, The Children’s Hospital of Philadelphia, Philadelphia, PA
Ana Catarina Martins
3iNOVA4Health, Nova Medical School, Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Lisbon, Portugal
Ariel Rivera
1Division of Hematology, Department of Pediatrics, The Children’s Hospital of Philadelphia, Philadelphia, PA
Nolan Hamilton
1Division of Hematology, Department of Pediatrics, The Children’s Hospital of Philadelphia, Philadelphia, PA
Pankja Sharma
1Division of Hematology, Department of Pediatrics, The Children’s Hospital of Philadelphia, Philadelphia, PA
Yelena Z. Ginzburg
Division of Hematology and Medical Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai
Carlo Castruccio Castracani
4The Children's Hospital of Philadelphia, Philadelphia, United States
Carla Casu
1Division of Hematology, Department of Pediatrics, The Children’s Hospital of Philadelphia, Philadelphia, PA
Ritama Gupta
1Division of Hematology, Department of Pediatrics, The Children’s Hospital of Philadelphia, Philadelphia, PA
Raffaella Gozzelino
3iNOVA4Health, Nova Medical School, Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Lisbon, Portugal
Edward M. Behrens
5Division of Rheumatology, Department of Pediatrics, The Children’s Hospital of Philadelphia, Philadelphia, PA
Laura F. Bennett
6Center for Molecular Immunology and Infectious Disease, The Pennsylvania State University, University Park, PA
Robert F. Paulson
6Center for Molecular Immunology and Infectious Disease, The Pennsylvania State University, University Park, PA
Peter Kurre
1Division of Hematology, Department of Pediatrics, The Children’s Hospital of Philadelphia, Philadelphia, PA
Stefano Rivella
4The Children's Hospital of Philadelphia, Philadelphia, United States