y www.nature.com/scientificreports/ only the expression of surface markers of neutrophil exhaustion but also for the related swarming phenotype associated with neutrophil exhaustion.

Low-grade inflammatory monocytes critically contribute to the pathogenesis of chronic inflammatory diseases such as atherosclerosis. The elevated expression of coactivating molecule CD40 as well as key adhesion molecule CD11a is a critical signature of inflammatory monocytes from both human patients with coronary artery diseases as well as in animal models of atherosclerosis. In this study, we report that subclinical superlow-dose LPS, a key risk factor for low-grade inflammation and atherosclerosis, can potently trigger the induction of CD40 and CD11a on low-grade inflammatory monocytes. Subclinical endotoxin-derived monocytes demonstrate immune-enhancing effects and suppress the generation of regulatory CD8+CD122+ T cells, which further exacerbate the inflammatory environment conducive for chronic diseases. Mechanistically, subclinical endotoxemia activates TRAM-mediated signaling processes, leading to the activation of MAPK and STAT5, which is responsible for the expression of CD40 and CD11a. We also demonstrate that TRAM-mediated monocyte polarization can be suppressed by IRAK-M. IRAK-M–deficient monocytes have increased expression of TRAM, elevated induction of CD40 and CD11a by subclinical-dose endotoxin, and are more potent in suppressing the CD8 regulatory T cells. Mice with IRAK-M deficiency generate an increased population of inflammatory monocytes and a reduced population of CD8 T regulatory cells. In contrast, mice with TRAM deficiency exhibit a significantly reduced inflammatory monocyte population and an elevated CD8 T regulatory cell population. Together, our data reveal a competing intracellular circuitry involving TRAM and IRAK-M that modulate the polarization of low-grade inflammatory monocytes with an immune-enhancing function.

Neutrophils are the dominant leukocytes in circulation and the first responders to infection and inflammatory cues. While the roles of neutrophils in driving inflammation have been widely recognized, the contribution of neutrophils in facilitating inflammation resolution is under-studied. Here, through single-cell RNA sequencing analysis, we identified a subpopulation of neutrophils exhibiting pro-resolving characteristics with greater Cd200r and Cd86 expression at the resting state. We further discovered that 4-PBA, a peroxisomal stress-reducing agent, can potently train neutrophils into the resolving state with enhanced expression of CD200R, CD86, as well as soluble pro-resolving mediators Resolvin D1 and SerpinB1. Resolving neutrophils trained by 4-PBA manifest enhanced phagocytosis and bacterial-killing functions. Mechanistically, the generation of resolving neutrophils is mediated by the PPARγ/LMO4/STAT3 signaling circuit modulated by TLR4 adaptor molecule TRAM. We further demonstrated that genetic deletion of TRAM renders the constitutive expansion of resolving neutrophils, with an enhanced signaling circuitry of PPARγ/LMO4/STAT3. These findings may have profound implications for the effective training of resolving neutrophils with therapeutic potential in the treatment of both acute infection as well as chronic inflammatory diseases.

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Graphical Abstract Discussion on neutrophil CD11d's potential role in facilitating neutrophil survival and macrophage efferocytosis during sepsis.