Interleukin-1β induced activation of the hypothalamus–pituitary–adrenal axis is dependent on interleukin-1 receptors on non-hematopoietic cells

Abstract

The proinflammatory cytokine interleukin-1β (IL-1β) plays a major role in the signal transduction of immune stimuli from the periphery to the central nervous system, and has been shown to be an important mediator of the immune-induced stress hormone release. The signaling pathway by which IL-1β exerts this function involves the bloodbrain-barrier and induced central prostaglandin synthesis, but the identity of the bloodbrain-barrier cells responsible for this signal transduction has been unclear, with both endothelial cells and perivascular macrophages suggested as critical components. Here, using an irradiation and transplantation strategy, we generated mice expressing IL-1 type 1 receptors (IL-1R1) either in hematopoietic or non-hematopoietic cells and subjected these mice to peripheral immune challenge with IL-1β. Following both intraperitoneal and intravenous administration of IL-1β, mice lacking IL-1R1 in hematopoietic cells showed induced expression of the activity marker c-Fos in the paraventricular hypothalamic nucleus, and increased plasma levels of ACTH and corticosterone. In contrast, these responses were not observed in mice with IL-1R1 expression only in hematopoietic cells. Immunoreactivity for IL-1R1 was detected in brain vascular cells that displayed induced expression of the prostaglandin synthesizing enzyme cyclooxygenase-2 and that were immunoreactive for the endothelial cell marker CD31, but was not seen in cell positive for the brain macrophage marker CD206. These results imply that activation of the HPA-axis by IL-1β is dependent on IL-1R1s on nonhematopoietic cells, such as brain endothelial cells, and that IL-1R1 on perivascular macrophages are not involved. Matsuwaki et al., p. 3

Ketamine Alleviates Depressive-Like Behaviors <i>via</i> Down-Regulating Inflammatory Cytokines Induced by Chronic Restraint Stress in Mice

“…It should be mentioned that pro-inflammatory cytokines may activate the HPA axis directly to augment the stress response. 26,27) CRS lead to the depressive behaviors in mice, which were associated with increase in pro-inflammatory cytokines as demonstrated in our results. One possible pathway by which inflammatory stimuli contribute to depression is to deplete tryptophan synthesis and reduce 5-hydroxytryptamine (5-HT) via activating indoleamine 2,3-dioxygenase (IDO).…”

Talking to the Brain at the Blood-Brain Barrier through Inflammation-Induced Prostaglandin E2

“…Some examples are COX-2 (Cao et al, 1995;Engström et al, 2012; Inoue et al, 2002), mPGES-1 (Ek et al, 2001;, IL-1R1 Ek et al, 2001;Konsman et al, 2004;Matsuwaki et al, 2014), IkBα (Laflamme et al, 1999;Quan et al, 1997), and inducible lipocalin-2 (Hamzic et al, 2013a) in endothelial cells, and thromboxane-A synthases-1 (Tbxas1) in perivascular macrophages (Cyrus et al, 2010;Gabrielsen et al, 2010). Furthermore, functional coupling of increased production (COX-2, mPGES-1) and decreased degradation (15-PGDH) as revealed here was also previously reported to occur for PGE2 (Hahn et al, 1998;Tai et al, 2006).…”

“…In this thesis though few measurements were done at protein level as the LPS mouse model used (paper I-IV) has been extensively characterized in our laboratory for e.g. COX-2, lipocaline-2, cytokines and PGE2 expression, and cortisol release (Elander et al, 2009;Nilsberth et al, 2009a), and recently also for IL-1R1 (Matsuwaki et al, 2014) and mPGES-1 .…”

“…The same strategy has been used by others to investigate the contribution to the sickness syndrome of hematopoietic vs. non-hematopoietic expression of TLR4 (Chakravarty and Herkenham, 2005;Steiner et al, 2006a), MyD88 (Gosselin and Rivest, 2008;Ruud et al, 2013b), and IL-1R1 (Matsuwaki et al, 2014).…”

“…Two main opposing views emerged, one supporting the endothelial cells (Cao et al, 1995;Ek et al, 2001;Matsumura et al, 1998;Yamagata et al, 2001) and the other favoring the perivascular macrophages (Breder and Saper, 1996;Elmquist et al, 1997a;Schiltz and Sawchenko, 2002). To address this question, we (paper I) Hamzic et al, 2013b;Matsuwaki et al, 2014;Wilhelms et al, 2014) and other groups (Chakravarty and Herkenham, 2005;Ching et al, 2007;Gosselin and Rivest, 2008;Ridder et al, 2011) have developed complex transgenic mice models that allowed in vivo analysis of one gene in a BBB cell population at a time (reviewed with paper I).…”