Trained Memory of Uterine Macrophages Improves Subsequent Pregnancy Outcomes

ABSTRACT A previously successful pregnancy promotes the fitness of subsequent pregnancies, of which the pregnancy‐induced memory is ascribed exclusively to adaptive lymphocytes. However, whether macrophages at maternal‐fetal interface acquire pregnancy‐specific immune memory remains unclear. Using human decidual samples and complementary mouse models, we identify human leukocyte immunoglobulin‐like receptor subfamily B3 ⁺ (LILRB3 ⁺ ) and murine paired immunoglobulin‐like receptor B ⁺ (PIR‐B ⁺ ) macrophages as a uterine memory subset, which expands progressively with gravidity and gestational age, and exhibits paternal specific immune memory. In both species, these cells exhibited hallmarks of pregnancy‐induced trained tolerance, including elevated IL‐10, TGF‐β, and CD206, together with reduced CD80/CD86 expression and suppression of pro‐inflammatory cytokines. Mechanistically, PIR‐B‐SHP signaling drives macrophage metabolic reprogramming to oxidative phosphorylation/fatty acid oxidation for the formation of memory. Moreover, adoptive transfer of PIR‐B ⁺ uterine macrophages into abortion‐prone mouse models significantly improves pregnancy outcomes, highlighting their therapeutic potential. Together, our findings uncover a previously unrecognized form of decidual macrophage trained memory in an antigen‐specific manner, which opens avenues for therapeutic strategies aimed at preventing or reducing recurrent pregnancy loss.