Tissue macrophages stem sepsis induced altered organ repair

Abstract

IntroductionSepsis, the most severe manifestation of infection, remains both common and life-threatening. Beyond the acute phase, growing evidence highlights that sepsis survivors face an increased risk of chronic organ dysfunction, including kidney and heart failure. While early immune mechanisms of sepsis have been extensively studied, the biological processes underlying delayed post-sepsis organ sequelae remain poorly understood. MethodsUsing murine models of sepsis, we investigated the long-term impact of sepsis on organ immune landscapes and tissue repair. Fate-mapping experiments were conducted to trace macrophage origin and persistence. Single-cell RNA sequencing of the heart and kidney was performed to characterize macrophage subpopulations and transcriptional reprogramming following sepsis. Functional consequences of this immune remodeling were assessed by challenging post-septic animals with angiotensin II to evaluate secondary injury susceptibility and fibrotic remodeling. ResultsSepsis induced transient multiorgan failure but led to a sustained expansion of tissue macrophages. Fate-mapping demonstrated that this expansion was largely driven by the recruitment and engraftment of monocyte-derived macrophages. Single-cell transcriptomic analyses revealed that post-septic macrophages acquired a distinct proinflammatory and profibrotic signature, consistent with persistent microenvironmental activation. Functionally, this altered macrophage landscape impaired organ resilience, as evidenced by increased mortality and exacerbated cardiac and renal fibrosis upon secondary challenge. DiscussionOur findings identify macrophage reprogramming as a central mechanism linking sepsis to long-term organ vulnerability. The persistence of monocyte-derived macrophages with maladaptive transcriptional profiles promotes fibrotic remodeling and impaired tissue repair. Targeting macrophage recruitment or reprogramming may represent a promising strategy to prevent chronic organ failure among sepsis survivors. SIGNIFICANCE STATEMENTSepsis survivors often develop chronic organ dysfunction, yet the mechanisms linking acute infection to long-term damage remain unclear. We show that sepsis triggers expansion of inflammatory and profibrotic macrophages derived from bone marrow precursors in the kidney and heart. These alterations were associated with impaired organ resilience to subsequent injury, which suggest macrophage-driven maladaptive repair as a potential target to improve long-term outcomes after sepsis.