Abstract
Background: In HIV patients on combination antiretroviral therapy (cART), persistent systemic inflammation is a driving force for the progression of comorbidities, such as cardiovascular diseases. Monocyte and macrophage-related inflammation rather than T cell activation is a major cause of chronic inflammation. However, the underlying mechanism of how monocytes cause persistent inflammation is multifaceted. Methods and Results: In vitro, we demonstrated that lipopolysaccharides (LPS) or tumor necrosis factor alpha (TNFα), induced a robust increase of Delta-like ligand 4 (Dll4) mRNA and protein expression in human monocytes and Dll4 secretion (extracellular Dll4, exDll4) from monocytes. Enhanced Dll4 expression in monocytes triggered Notch1 activation to promote pro-inflammatory factors expression. Dll4 silencing and inhibition of Nocth1 activation diminished the LPS or TNFα -induced inflammation. exDll4 releases in response to cytokines occurred in monocytes but not endothelial cells or T cells. In clinical specimens, we found that people living with HIV (PLWH), both male and female, on cART showed a significant increase in membrane-bound Dll4 (mDll4) expression, activation of Dll4-Notch1 signaling, and inflammation in monocytes. Surprisingly, plasma exDll4 was remarkably elevated in HIV male patients but not female patients, and its levels paralleled with monocytes mDll4 in HIV male patients. In addition, circulating exDll4 was positively associated with pro-inflammatory monocytes and negatively associated with classic monocytes in HIV male patients. Conclusion: Pro-inflammatory stimuli increase Dll4 expression and Dll4-Notch1 signaling activation in monocytes and enhance monocyte inflammation, contributing to persistent systemic inflammation in PLWH. Plasma exDll4 is mainly released from monocytes and could act as a potential biomarker of HIV-related cardiovascular diseases caused by monocyte-mediated inflammation in HIV male patients. mDll4 in monocytes could be a potential biomarker of inflammation for both genders of HIV patients.
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