<p>Depression is highly prevalent among older people globally. It is well known that childhood trauma and loneliness are significant risk factors for depression, and neural alterations in the default mode network and immunological dysregulation (e.g., neutrophil-to-lymphocyte ratio) are factors significantly associated with loneliness and depression. This study examined the inter-relationships and interactions of these factors for translational insight into the pathophysiological underpinnings of late-life depression. Among ninety-two healthy older adults, we measured the leukocyte distribution as reflected by neutrophil-to-lymphocyte ratio, childhood trauma history, current feelings of loneliness, and levels of depressive symptoms. All participants underwent structural MRI scanning to acquire T1-weighted images, which were used to measure the grey matter volume within the default mode network and its key regions. We observed that loneliness as a significant mediator explained the positive relationship between childhood emotional neglect and the severity of depression in late life. The modulating effect of grey matter volume in the default mode network depends on the level of neutrophil-to-lymphocyte ratio. In sum, our findings indicated that the more severe the lonely feeling those older people with childhood emotional neglect felt, the more the depressive symptoms were, which was especially obvious among those with relatively higher neutrophil-to-lymphocyte ratio and with lower grey matter volume in the default mode network. The current findings inspire future preventive and interventional studies targeting loneliness and inflammation to promote mental wellness in older adults.</p>