Slfn4-mediated Stat3 signaling promotes suppressive bone marrow monocytes in a murine second-hit sepsis model
Abstract
Background: Sepsis survivors who develop recurrent or secondary infections often exhibit prolonged immunosuppression and impaired pathogen clearance, yet the underlying mechanisms remain poorly defined and targeted therapies are limited.
Methods: We established a murine second-hit sepsis model to examine immune remodeling during the immunosuppressive phase after an initial inflammatory insult. Bone marrow immune remodeling was characterized by flow cytometry and single-cell RNA sequencing. Purified myeloid subsets were subjected to functional assays, transcriptomic analyses, and molecular studies to define how Slfn4 regulates the suppressive program of monocytic myeloid-derived suppressor cell-like (M-MDSC-like) cells.
Results: We found that Slfn4 marks an immunosuppressive M-MDSC-like subset in the bone marrow during second-hit sepsis, and our data support a role for the Slfn4-Stat3 axis in maintaining its suppressive phenotype. Genetic silencing of Slfn4 or pharmacologic inhibition of Stat3 was associated with reduced M-MDSC-like cell abundance, partially restored T-cell function, and improved survival. Mechanistically, our data supports a model in which SLFN4 enhances Stat3 activation in association with post-transcriptional repression of Socs3, potentially through interaction with an AU-rich element within the Socs3 3'-UTR. In addition, sildenafil, a PDE5 inhibitor, decreased M-MDSC-like cell abundance and enhanced bacterial clearance in vivo.
Conclusions: These findings…
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