Macrophage depletion paradoxically increased early neuroinflammation after MI, and subsequent neutrophil inhibition increased the incidence of left ventricle rupture in mice.
Does macrophage depletion or neutrophil inhibition alter neuroinflammation and ventricle remodeling after myocardial infarction in mice?
Intact neutrophil-macrophage signaling is essential for myocardial repair after MI, and PET imaging can effectively track post-MI inflammation in both the heart and brain.
Different immune cell populations influence the severity of cardiac inflammation after myocardial infarction (MI), which predicts subsequent heart failure. Concurrent neuroinflammation after MI may contribute to heightened risk of cognitive impairment, but the underlying mechanisms remain unclear. We characterized the role of macrophages and neutrophils in concurrent neuroinflammation after acute MI using PET. Methods: C57BL/6N mice underwent permanent coronary artery ligation to induce MI. To modulate specific immune populations, peripheral macrophages were depleted using clodronate-loaded liposomes, and neutrophils were inhibited using a neutralizing antibody against Ly6G. Serial molecular PET imaging of mitochondrial translocator protein (TSPO) visualized inflammation in the heart and brain over 8 wk. Ventricle geometry and contractile function were assessed by cardiac MRI. Results: Acute MI induced microglial activation identified by increased TSPO PET signal in the global brain in parallel with infarct region inflammation. Macrophage depletion before injury ablated macrophage content in the left ventricle on TSPO PET and histopathology but paradoxically increased the neuroinflammation signal in the first week after MI. Persistent neutrophil activity in the left ventricle of macrophage-depleted animals suggested a role for granulocytes in mediating heart–brain immune cell cross-talk. However, antibody-mediated inhibition of neutrophil activity before or at 24 h after MI did not reduce acute neuroinflammation but rather increased incidence of left ventricle rupture. Flow cytometry identified accelerated monocyte repopulation in the damaged left ventricle after macrophage depletion and subsequent neutrophil inhibition, underscoring the interaction between these immune cell populations in post-MI healing. Conclusion: Intact neutrophil–macrophage signaling is essential for effective myocardial repair after ischemic injury, but neutrophil persistence does not independently regulate neuroinflammation after MI. Nonetheless, PET imaging sensitively monitors response to immunomodulatory intervention and enables tracking of therapeutic efficacy at the site of injury and distant organ systems.
Lolatte et al. (2026) studied Myocardial Infarction and Neuroinflammation. Macrophage depletion (clodronate liposomes) and neutrophil inhibition (anti-Ly6G antibody) was evaluated on Inflammation in the heart and brain (TSPO PET signal) and ventricle geometry/contractile function. Macrophage depletion paradoxically increased early neuroinflammation after MI, and subsequent neutrophil inhibition increased the incidence of left ventricle rupture in mice.