Slfn4-mediated Stat3 signaling promotes suppressive bone marrow monocytes in a murine second-hit sepsis model

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.

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.

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.

These findings implicate the Slfn4-Stat3 axis in bone marrow-associated immunosuppression in this murine second-hit sepsis model and support further investigation of this pathway in the late immunosuppressive phase of sepsis.