Repeated Social Defeat, Neuroinflammation, and Behavior: Monocytes Carry the Signal

Abstract

Mounting evidence indicates that proinflammatory signaling in the brain affects mood, cognition, and behavior and is linked with the etiology of psychiatric disorders, including anxiety and depression. The purpose of this review is to focus on stress-induced bidirectional communication pathways between the central nervous system (CNS) and peripheral immune system that converge to promote a heightened neuroinflammatory environment. These communication pathways involve sympathetic outflow from the brain to the peripheral immune system that biases hematopoietic stem cells to differentiate into a glucocorticoid-resistant and primed myeloid lineage immune cell. In conjunction, microglia-dependent neuroinflammatory events promote myeloid cell trafficking to the brain that reinforces stress-related behavior, and is argued to play a role in stress-related psychiatric disorders. We will discuss evidence implicating a key role for endothelial cells that comprise the blood-brain barrier in propagating peripheral-to-central immune communication. We will also discuss novel neuron-to-glia communication pathways involving endogenous danger signals that have recently been argued to facilitate neuroinflammation under various conditions, including stress. These findings help elucidate the complex communication that occurs in response to stress and highlight novel therapeutic targets against the development of stress-related psychiatric disorders.

Figure 1

Overview of stress-induced myelopoiesis and monocyte trafficking to the CNS. Social defeat stress activates fear/threat appraisal circuitry. In corresponding regions, microglia are activated and increase proinflammatory cytokine and chemokine expression that interacts with BBB-derived endothelial cells to recruit circulating monocytes. Social defeat also initiates brain-to-immune outflow via SNS and HPA axis activation. SNS and HPA activation shifts peripheral immune responses through production of primed and GC-insensitive monocytes from the bone marrow into circulation. These monocytes have an increased capacity to traffic throughout the body and interact with BBB endothelial cells to traffic into the CNS.

Figure 2

Stress-responsive neuroendocrine pathways alter homeostatic hematopoiesis: enhanced myelopoiesis leads to production of primed and GC-resistant myeloid cells. (a) Hematopoietic stem cells (HPSCs) begin with the capacity to differentiate into myeloid or lymphocyte progenitor cells. With the focus on myeloid lineage, myeloid progenitor cells differentiate into erythroid–megakaryocyte (MK) progenitor cells or granulocyte-macrophage colony-forming unit (GM-CFU). GM-CFU differentiates into basophils, neutrophils, eosinophils, and monocytes. Monocytes further differentiate into Ly6C^hi expression that is associated with elevated expression of proinflammatory molecules and increased ability to traffic to tissue (ie, inflammatory). Ly6C^lo monocytes are associated with increased expression of anti-inflammatory molecules and tissue repair (ie, patrolling). (b) Stress exposure can influence myelopoiesis via descending sympathetic nerve fibers that innervate lymphoid tissue. Increased NE alters growth factors (GM-CSF) and chemokines (CXCL12) that promote GM-CFU differentiation to primed/GC-resistant Ly6C^hi monocytes.

Figure 3

Reactive endothelium facilitates stress-induced monocyte trafficking to the CNS. Exposure to stress upregulates adhesion molecules that assist in the capture and extravasation of peripherally derived monocytes into perivascular and parenchymal monocytes. Rolling/capture occurs via PSGL-1/P-selectin and L-selectin/E-selectin interactions. Activated microglia release cytokines (IL-1β) and chemokines (CCL2) that promote monocyte arrest via ICAM/VCAM-mediated events. Accumulation of peripherally derived monocytes in the CNS converge with resident microglia to increase neuroinflammatory signaling (ie, IL-1β). In addition, endothelial cells secrete cytokines and prostaglandins that propagate neuroinflammation. Excess release of IL-1β is implicated in the prolonged behavioral response of stress.

Figure 4

Stress-induced danger signals propagate neuroinflammation. Danger signals are released in stress-responsive brain regions to activate resident microglia. HMGB1 signals through Toll-like receptors to translocate NF-κB to the nucleus that drives transcription of pro-IL-1β and NLRP3. ATP binds to P2X₇ and initiates K⁺ efflux from the cell. In turn, NLRP3 forms a multiprotein complex with ASC and pro-caspase-1 termed the inflammasome. Pro-caspase-1 is cleaved to the bioactive caspase-1 that cleaves pro-IL-1β to mature IL-1β. Released IL-1β interacts with IL-1 receptors located on (1) endothelial cells to induce a reactive endothelium that facilities recruitment of monocytes and (2) neurons to promote the behavioral response of stress.