LIF and Oncostatin M mitigate LPS-induced acute endometritis via distinct immunoregulatory mechanisms in peritoneal macrophages in vivo

<h2>Summary</h2> Acute endometritis, often triggered by Gram-negative bacterial endotoxins such as lipopolysaccharide (LPS), disrupts endometrial integrity, induces robust pro-inflammatory macrophage activation, and compromises uterine function, potentially leading to infertility and adverse pregnancy outcomes. Here, we demonstrate that IL-6 family cytokines, Leukemia Inhibitory Factor (LIF) and Oncostatin M (OSM), exert complementary yet distinct immunoregulatory effects that mitigate LPS-induced acute endometritis <i>in vivo</i>. Both cytokines preserved endometrial architecture, limited neutrophil and macrophage infiltration, suppressed cytotoxic iNOS expression, and promoted macrophage-mediated tissue repair, with OSM providing superior systemic and hepatoprotective effects. Mechanistically, these outcomes were linked to STAT3-dependent Mφ reprogramming toward anti-inflammatory M2 phenotypes, with OSM additionally engaging SMAD2 pathways to favor CD163 M2 macrophages marker, whereas LIF preferentially induced anti-inflammatory M2 subsets engaging STAT3 alone. Our findings highlight the therapeutic potential of LIF and OSM as modulators of uterine immune homeostasis and macrophage plasticity modulating and mitigating LPS-acute endometritis and preserving endometrial integrity.