Neudesin, a secretory protein, attenuates activation of lipopolysaccharide-stimulated macrophages by suppressing the Jak/Stat1/iNOS pathway

Neudesin, a heme-binding protein previously identified for its neurotrophic activity, has been implicated in various physiological and pathological processes, including immune regulation. However, its role in inflammatory macrophages remains unclear. Herein, we investigated the function of neudesin in the regulation of inflammatory macrophages. In vitro experiments were performed in bone marrow-derived macrophages (BMDMs). In vivo experiments were conducted on neudesin knockout mice with a murine endotoxic shock model. We observed that neudesin deficiency led to elevated expression of Nos2/iNOS and increased nitric oxide (NO) production in lipopolysaccharide (LPS)-stimulated BMDMs. Further, we found that neudesin, via the ERK/MAPK signaling pathway, promotes the proteasome-mediated degradation of Stat1, resulting in suppression of NO production. Furthermore, neudesin-deficient mice exhibited higher mortality rates following LPS administration, accompanied by increased Nos2/iNOS expression and nitrated proteins in the heart, compared to that in wildtype mice. Treatment with an iNOS inhibitor drastically improved the survival rate of neudesin-deficient mice, highlighting the significance of neudesin-mediated iNOS signaling in modulating immune responses and preventing excessive inflammation. Our findings suggest that neudesin acts as an anti-inflammatory cytokine, suppressing NO production in inflammatory macrophages, underscoring its potential as a therapeutic target for immune-related disorders. [Display omitted] •Neudesin inhibits Nos2/iNOS expression and NO in LPS-stimulated BMDMs.•Neudesin inhibits the Jak/Stat1 pathway by promoting Stat1 degradation via the ubiquitin-proteasome system in BMDMs.•Neudesin promotes Stat1 degradation through the MEK/ERK signaling pathway.•Neudesin-deficient mice show increased LPS-induced lethality with higher iNOS expression and protein nitration in the heart.