TNFα Plays Essential Role in Resolution of Anemia of Inflammation in Tnfαko Mice Treated with Heat-Killed Brucella Abortus

• Published in: Blood 2024-11, Vol.144, p.168-168
• Main Authors: Lo Presti, Vania, Chen, Ding-wen, Martins, Ana, Sharma, Pankaj, Ginzburg, Yelena, Castruccio Castracani, Carlo, Casu, Carla, Gupta, Ritama, Gozzelino, Raffaella, Behrens, Edward, Bennett, Laura F, Paulson, Robert, Kurre, Peter, Rivella, Stefano, Guerra, Amaliris
• Format: Article
• Language: English
• ISSN: 0006-4971
• DOI: 10.1182/blood-2024-212272

Anemia of inflammation (AI) is the second most prevalent form of anemia, and is common in patients with chronic inflammatory states, such as infection, autoimmunity, and cancer. There are no targeted treatments available for AI, strategies typically focus on treating the underlying disease. Inhibiting tumor necrosis factor-α (TNFα) has become the gold standard for treating autoimmune disorders. However, some patients show exacerbations or onsets of new autoimmune conditions following treatment. We became interested in the effects of TNFα on erythropoiesis due to reports of TNFα blocking antibodies (Ab) improving anemia as a secondary treatment outcome. We started our studies using a well-established model of AI induced by injection of heat-killed Brucella Abortus (BA) in germline TNFα knockout (TNFαKO) mice. Our findings show that TNFαKO+BA mice developed a macrocytic hyperchromic anemia, leukocytosis, and abnormally increased myeloid and lymphocytes populations in the bone marrow (BM) and spleens, which resulted in death after 10-weeks. Serum cytokine analysis of TNFαKO+BA mice displayed sustained elevations of interleukin (IL)12p40 and interferon-γ (IFNγ) levels. Given the reports of improvements in anemia in patients treated with TNFα blocking agents, these surprising findings made us question whether TNFα played an unknown anti-inflammatory role which impacted erythropoiesis.IFNγ's role in RBC lifespan, erythrophagocytosis, and BM failure is well-established. We hypothesized that TNFα played an important anti-inflammatory role in modulating IFNγ. IFNγKO+BA mice showed normal TNFα serum levels, a reduced inflammation profile, normal red blood cell (RBC) counts and minimal perturbations to erythropoiesis at time points tested. Additionally, a TNFαKO/IFNγKO double knock-out (DKO) mouse line was generated and challenged with BA to test if lack of IFNγ would correct the TNFαKO+BA phenotype. Indeed, DKO+BA mice had a phenotype closer to that of IFNγKO+BA and WT+BA than TNFαKO+BA. We tested if administration of recombinant TNFα (rTNFα) would correct the chronic AI phenotype in TNFαKO+BA. TNFαKO+BA treated with rTNFα died shortly after administration. We also tested if reduction of IFNγ by an anti-IFNγ Ab would rescue TNFαKO+BA mice. We found that treatment with anti-IFNγ Ab partially corrected the anemia phenotype but reverted after 4 weeks. However, rTNFα in combination with anti-IFNγ Ab reversed the hyper-inflammatory phenotype, rescued erythropoiesis, and