Depletion of macrophage reduces the negative impact of bone fracture on stroke injury. A, Representative picture taken in the periinfarct region (bregma 1.3 mm) of mice treated with control liposome (A1, control liposome [CT-lip]) and clodrolip (A2). Scale bar: 100 μm. B, A bar graph shows the quantification of CD68⁺ cells in the periinfarct region (n = 7, * P < 0.001). C, Quantification of infarct volume (n = 7, * P < 0.001). D, Quantification of adhesive removal time of the right paw (n = 10, * P < 0.001). E, Quantification of the percentage of left turn (n = 10, * P < 0.001). F, Synthesis of possible mechanisms underlying the negative impact of bone fracture on stroke injury: 1, Alarmins including high-mobility-group box chromosomal protein-1 (HMGB1) is released into blood after bone fracture. 2, HMGB1 interacts with its receptors on innate immune cells including macrophages. 3, Systemic macrophages are recruited to the stroke lesion site in the brain; together with activated microglia, they release neurotoxic molecules. 4, Exacerbation of neuroinflammation, neuronal cell death, and behavioral dysfunction. 5, Increased neuronal death further increases the release of alarmins and chemokines, triggering a vicious cycle through HMGB1–macrophage activation. DAPI = 4’,6-diamidino-2-phenylindole.