Brain Perivascular Macrophages Do Not Mediate Interleukin-1-Induced Sickness Behavior in Rats

Abstract

Sickness behavior, characterized by on overall reduction in behavioral activity, is commonly observed after bacterial infection. Sickness behavior can also be induced by the peripheral administration of Gram-negative bacterial lipopolysaccharide (LPS) or interleukin-1beta (IL-1β), a pro-inflammatory cytokine released by LPS-activated macrophages. In addition to the microglia, the brain contains perivascular macrophages, which express the IL-1 type 1 receptor (IL-1R1). In the present study, we assessed the role of brain perivascular macrophages in mediating IL-1β-induced sickness behavior in rats. To do so, we used intracerebroventricular (icv) administration of an IL-1β-saporin conjugate, known to eliminate IL-R1-expressing brain cells, prior to systemic or central IL-1β injection. Icv IL-1β-saporin administration resulted in a reduction in brain perivascular macrophages, without altering subsequent icv or ip IL-1β-induced reductions in food intake, locomotor activity, and social interactions. In conclusion, the present work shows that icv IL-1β-saporin administration is an efficient way to target brain perivascular macrophages, and to determine whether these cells are involved in IL-1β-induced sickness behavior.

Keywords: brain perivascular macrophages; food intake; interleukin-1; locomotor activity; social interaction.

Figure 1

Effects of intracerebroventricular IL-1ß-saporin conjugate administration on brain perivascular cells in the organum vasculosum laminae terminalis (OVLT; A,C,D) and amygdala (B,E,F). In these structures, the IL-1ß-saporin conjugate reduced the number of CD163 immunoreactive (CD163 i.r.) cells (A–F) without affecting labelling for the endothelial cell marker von Willebrand factor (C,D) and the astrocyte marker glial fibrillary acidic protein (E,F). Brown labeling indicates von Willebrand factor (C,D) and glial fibrillary acidic protein (E,F) and black staining CD163. * p < 0.05; *** p < 0.001. IL1-SAP compared to IL1 + SAP group. IL1: interleukin-1ß; IL1-SAP: interleukin-1ß conjugated to saporin; IL1 + SAP: interleukin-1ß not conjugated to saporin; PBS: phosphate-buffered saline; SAP: saporin. Group sizes: n = 5–9. Scale bar represents 100 µm.

Figure 2

Effects of intracerebroventricular IL-1ß-saporin conjugate administration on subsequent IL-1β-induced sickness behavior. Intracerebroventricular pre-treatment with IL-1β-saporin conjugate did not affect the reduction in food intake and social interaction after intracerebroventricular IL-1ß administration (A,B). Intracerebroventricular administration of IL-1β-saporin conjugate did not affect the reduction in food intake and locomotor activity to subsequent intraperitoneal IL-1ß injection (C,D). IL1: interleukin-1ß; IL1-SAP: interleukin-1ß conjugated to saporin; IL1 + SAP: interleukin-1ß not conjugated to saporin; PBS: phosphate-buffered saline; Sal: saline; SAP: saporin. Group sizes: n = 5–9.