TNFα signaling restores steady-state hematopoiesis in a TNFαKO mouse model of anemia of inflammation Available to Purchase

• Germline deletion of Tnfα results in irreversible anemia in an anemia of inflammation mouse model

• TNFα plays an important role in restoring steady-state erythropoiesis after inflammatory event

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 (IL6) is well-known to induce the iron-sequestering hormone hepcidin, which results in iron-restricted anemia. The contributions of other pro-inflammatory cytokines such as tumor necrosis factor-α (TNFα) and interferon-γ (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 germline 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 pro-inflammatory IL12p40 and IFNγ cytokines that did not resolve. However, IFNγKO and TNFαKO/FNγKO double knock-out (DKO) mice showed reduced inflammation and anemia following HKBA administration. Since 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 hyper-inflammatory phenotype, restored erythropoiesis, and prevented death of TNFαKO+HKBA mice. Our data provides compelling evidence for an anti-inflammatory role of TNFα that is necessary for the restoration of erythropoiesis and mitigation of pro-inflammatory IFNγ action in a mouse model of AI.