Macrophage reprogramming and functional plasticity in sepsis

Sepsis remains one of the leading causes of mortality worldwide, driven not by the infection itself but by a dysregulated host response that spirals into a cytokine storm and subsequent immune paralysis. This maladaptive immune reaction frequently culminates in life-threatening complications, including multiple organ failure and acute lung injury. Among the immune cells orchestrating this process, macrophages serve as pivotal sentinels of the innate immune system, coordinating inflammatory and reparative programs in response to microbial and endogenous cues. Increasing evidence now reveals that their behavior during sepsis is profoundly shaped by epigenetic regulation. Dynamic changes in DNA methylation, histone modifications, and non-coding RNAs fine-tune macrophage activation, polarization, and memory throughout the septic course. This review will dissect how these epigenetic programs dictate the initiation, progression, and resolution of sepsis, integrating recent discoveries to clarify underlying mechanisms and highlight promising epigenetic targets for therapeutic intervention.