The role of neutrophil granulocytes in immune-to-brain communication

Abstract

Immune-to-brain communication has been studied in a variety of experimental models. Crucial insights into signalling and mechanisms were previously revealed in studies investigating fever induction pathways. The scientific community has primarily focused on neuronal and humoral pathways in the manifestation of this response. Emerging evidence has now shown that immune-to-brain signalling via immune cells is pivotal for normal brain function and brain pathology. The present manuscript aims to provide a brief overview on the current understanding of how immune cells signal to the brain. Insights are summarized on the potential physiological significance of some immune cells signalling from the periphery to the brain. A particular focus is laid on the role of neutrophil granulocytes. As such, IL-1β expressing neutrophil granulocytes have been shown to transfer inflammatory information to the brain and contribute to prolonged behavioural changes due to septic encephalopathy in rats during severe systemic inflammation induced by the bacterial component and TLR4 agonist lipopolysaccharide. Modulation of immune cell recruitment to the brain is discussed by various confounding factors including sleep, exercise, the nutritional status e.g. obesity, leptin and omega 3 fatty acids, and psychological or inflammatory stressors. The physiological significance of immune cell mediated communication between the immune system and the brain is highlighted by the fact that systemic inflammatory insults can exacerbate ongoing brain pathologies via immune cell trafficking. New insights into mechanisms and mediators of immune cell mediated immune-to-brain communication are important for the development of new therapeutic strategies and the better understanding of existing ones. Abbreviations: ACTH: adrenocorticotropic hormone; BBB: blood-brain barrier; BBI: blood-brain interface; CD: cluster of differentiation; CINC: cytokine-induced neutrophil chemoattractant; CRH: corticotropin releasing hormone; CVOs: circumventricular organs; CXCR: chemokine receptor; DAPI: 40:6-diamidino-2-phenylindole dilactate; DHA: docosahexaenoid acid; ICAM: intracellular adhesion molecule; IL: interleukin; i.p.: intraperitoneal; i.v.: intravenous; KC: keratinocytes-derived chemokine; LPS: lipopolysaccharide; MIP: macrophage inflammatory protein; MS: multiple sclerosis; NFκB: nuclear factor kappa B; NF-IL6: nuclear factor IL-6; PCTR: protectin conjugates in tissue regeneration; PG: prostaglandin; p.i.: post injection; PVN: paraventricular nucleus; ra: receptor antagonist; STAT3: signal transducer and activator of transcription 3; TIMP: tissue inhibitors of metalloproteinases; TLR: toll-like receptor; TNFα: tumor necrosis factor alpha.

Keywords: Immune-to-brain communication; cytokines; extravasation; immune cell trafficking; inflammatory transcription factors; leptin; macrophages; neutrophil granulocytes; systemic inflammation.

Figure 1.

Simplified schematic illustration of immune-to-brain communication. Infection and inflammation stimulate immune cells to produce cytokines. These activate neuronal sensory afferences for example of the vagus nerve. Moreover, cytokines and immune cells directly act on the brain i.e. endothelial cells, brain structures with a leaky blood-brain barrier, namely, the circumventricular organs, meninges and the choroid plexus. Subsequently, brain-controlled sickness responses develop. In the paraventricular nucleus of the hypothalamus (PVN), corticotropin releasing hormone (CRH) is produced and released to stimulate the release of adrenocorticotropic hormone (ACTH) derived from the anterior pituitary into the circulation. ACTH induces an increase in glucocorticoids from the adrenal cortex. This hypothalamus-pituitary-adrenal-axis represents one of the endogenous feedback mechanisms to dampen systemic inflammation. Glucocorticoids are known to exhibit some of their effects dampening the activated immune system by inhibition of inflammatory transcription factors (partially adapted and modified from [112,113]).

Figure 2.

LPS-induced systemic inflammation increase ICAM1-immunoreactivity and induces the recruitment of neutrophil granulocytes to the brain in the paraventricular nucleus (PVN). LPS (5 mg/kg i.p., 4.5h) induces ICAM1-immunoreactivity (red, a-d) in the PVN (c) compared to controls (a). Close association of ICAM1-immunoreactivity with myeloperoxidase (green) staining (a-d) is depicted in insets (b, d). In addition, LPS-stimulation (2.5 mg/kg 24h) increased the number of Ly-6B.2 alloantigen (clone 7/4) stained neutrophil granulocytes in the PVN (red, f) compared to controls (e). Von Willebrand factor (green, e-f) depicts brain vasculature. Blue DAPI staining visualizes the surrounding tissue (blue, a-f). Scale bars represent 100µm and 10µm in insets. The previously unpublished microphotographs were adapted from our own previous studies [15,53].