Aim2 inflammasome dependent IL1β/IL-18/Gasdermin D signaling is required for initiation of stress erythropoiesis in anemia of inflammation 2258281

Abstract Introduction Anemia of inflammation (AI) accompanies chronic inflammatory diseases. While steady-state erythropoiesis makes ∼2.5 × 106 RBCs/s, inflammatory cytokines shift hematopoiesis toward myeloid effectors suppressing erythroid differentiation and causing AI. To sustain red-cell output stress erythropoiesis expands self-renewing stress erythroid progenitors (SEPs) that rapidly proliferate and differentiate into RBCs. We investigated Aim2 inflammasome control of early SEPs and caspase-1—dependent maturation of IL-1β/IL-18 and the pore-forming protein gasdermin D (GSDMD). Methods Primary mouse marrow was cultured in a two-phase stress-erythropoiesis system: an Epo-free hypoxic expansion phase (BMP4, Hedgehog, GDF15, SCF on macrophage stroma) yielding immature SEPs, followed by Epo-driven differentiation. Perturbations included recombinant IL-1β/IL-18, IL-18 neutralization, and marrow from Aim2⁻/⁻, Gsdmd⁻/⁻, or Il1r1⁻/⁻ mice. Proliferation (viable counts), phenotype (flow cytometry), and output (BFU-E/CFU-E) were measured. In vivo, heat-killed Brucella abortus (HKBA) induced sterile inflammatory anemia; hematocrit, spleen, and serum were profiled for AIM2/caspase-1/IL-1β/IL-18 and SEP abundance. Results Loss of AIM2 and GSDMD impaired proliferation of immature SEPs and reduced BFU-E. Deletion of Il1r1(Receptor for IL1β) or neutralization of IL-18 similarly decreased early SEP expansion, whereas exogenous IL-1β/IL-18 enhanced it. In-vitro,IL-1β increased IL-1R1 on SEPs and upregulated PU.1, enriched in the most immature subsets. In HKBA anemia, Aim2⁻/⁻ mice showed reduced hematocrits and contracted immature SEPs. Il1r1⁻/⁻ and Gsdmd-/- mice failed to mount an effective response due to defects in the splenic monocyte/macrophage population due to impaired IL-1β signaling. Conclusion The AIM2/GSDMD/IL-1β/IL-18 axis is a primary driver of early SEP expansion, mechanistically linking dsDNA sensing to cytokine maturation, IL-1R upregulation, and PU.1 modulation. Funding Source n/a Topic Categories Hematopoiesis and Immune System Development (HEM)