Accumulating evidence suggest that the immune system plays an important role in the pathophysiology of depression. As a fundamental factor in the provocation of depression, chronic stress is associated with dysregulated immunity and subsequent inflammation. While anti-inflammatory agents have been tested as antidepressants, with some success in a subset of depressed subjects, targeting a more specific immune mechanism could have greater response rate and be applicable to a wider range of patients. The complement system is part of the innate arm of immunity. Complement component 3 (C3), the converging point of the complement activation pathways plays critical roles in neuroinflammation. Microglia, the principal immune effector of the brain responsible for immunosurveillance and neuroprotection, use C3 pathway to regulate synapse development. Our recent study found increased expression of C3 in the prefrontal cortex (PFC) of both depressed suicide (DS) subjects and mouse model (chronic unpredictable stress, CUS) of depression. C3 signaling is mediated through its receptor, C3a receptor 1 (C3aR1). Both microglia and monocytes/macrophages (Mo/MFs) express C3aR1. Although our study showed attenuation of chronic stress- induced depressive-like behavior in C3aR1 knockout mice, these findings do not distinguish between C3aR1 in microglia and Mo/MFs. We hypothesize that microglial C3 activation mediates chronic stress-induced increases in depressive-like behavior and neuroinflammation. In supporting this, our published and preliminary studies found that C3 is highly expressed in Ionized calcium binding adaptor molecule1+ cells (Iba1, which represent endogenous microglia and potentially infiltrating brain macrophages) following CUS. Also, increased expression of C3 was found in in Iba1+ cells of PFC of DS subjects; (2) Inhibition of nuclear factor-kappa B (NF?B; a key regulator of inflammation implicated in depression) signaling attenuated CUS-induced increase in C3 protein levels in mouse PFC. This is in agreement with previous reports that C3 promoter contains two putative NF?B binding sites and C3 is a direct NF?B target; and (3) Depletion of microglia significantly attenuated CUS-induced C3 elevation, infiltration of monocytes and depressive-like behavior in mice. While these observations are exciting, several critical questions are raised. Whether NF?B signaling in microglia mediates chronic stress-induced increase in C3 expression? Whether microglial C3aR1 mediates stress- induced depressive-like behavior and neuroinflammation ? Whether increases in C3 expression are associated with microglia activation and monocyte infiltration in the PFC of depressed subjects, and are primarily related to depression or suicide? To address these questions, we will 1) investigate mechanisms by which chronic stress induces increases in C3 expression; 2) determine whether microglial C3aR1 deficiency attenuates CUS- induced monocyte recruitment, neuroinflammation and depressive-like behavior; and 3) quantify the relationship between C3, microglia activation, and monocyte infiltration in the PFC of depressed subjects.
The proposed project is relevant to public health because identification of the pathophysiological mechanisms underlying chronic stress-induced depressive-like behavior and neuroinflammation will lead to novel interventions, including complement-based inhibitors or antibody strategies in stress-related mental health disorders. Thus, the project is relevant to the mission and priorities of the National Institute of Mental Health of the National Institute of Health that pertains to advancing mechanistic approaches to understand fundamental processes relevant to depression.
