Inflammation‐ and tumor‐induced anorexia and weight loss require MyD88 in hematopoietic/myeloid cells but not in brain endothelial or neural cells

Abstract

Loss of appetite is a hallmark of inflammatory diseases. The underlying mechanisms remain undefined, but it is known that myeloid differentiation primary response gene 88 (MyD88), an adaptor protein critical for Toll-like and IL-1 receptor family signaling, is involved. Here we addressed the question of determining in which cells the MyD88 signaling that results in anorexia development occurs by using chimeric mice and animals with cell-specific deletions. We found that MyD88-knockout mice, which are resistant to bacterial lipopolysaccharide (LPS)-induced anorexia, displayed anorexia when transplanted with wild-type bone marrow cells. Furthermore, mice with a targeted deletion of MyD88 in hematopoietic or myeloid cells were largely protected against LPS-induced anorexia and displayed attenuated weight loss, whereas mice with MyD88 deletion in hepatocytes or in neural cells or the cerebrovascular endothelium developed anorexia and weight loss of similar magnitude as wild-type mice. Furthermore, in a model for cancer-induced anorexia-cachexia, deletion of MyD88 in hematopoietic cells attenuated the anorexia and protected against body weight loss. These findings demonstrate that MyD88-dependent signaling within the brain is not required for eliciting inflammation-induced anorexia. Instead, we identify MyD88 signaling in hematopoietic/myeloid cells as a critical component for acute inflammatory-driven anorexia, as well as for chronic anorexia and weight loss associated with malignant disease.

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

“…Using the irradiation and transplantation protocol employed here, a high level of replacement in blood and brain of native hematopoietic cells with transplanted cells has been shown by us previously (Engström et al, 2012;Hamzic et al, 2013;Ruud et al, 2013). In the present study, the proportion of GFP+ cells among the white blood cells in the different groups of chimeras was in average 84% (SEM 1%), as determined by flow cytometry (Fig.…”

“…Matsuwaki et al,p. 16 The irradiation and transplantation procedure used here has been employed by us in three previous studies (Engström et al, 2012;Hamzic et al, 2013;Ruud et al, 2013).…”

Role of Cardiac- and Myeloid-MyD88 Signaling in Endotoxin Shock

“…These data strongly suggests that MyD88 signaling in bone marrow-derived immune cells such as tissue macrophages and circulating neutrophils/monocytes are mainly responsible for mediating systemic as well as local cardiac cytokine production during endotoxin shock. In consistent with our observation, previous studies have demonstrated that MyD88 signaling in myeloid cells is responsible for acute inflammatory-driven anorexia 39 and local adrenal inflammation 40 in lipopolysaccharide-treated animals. Overproduction of multiple inflammatory mediators, cytokines in particular, has been closely associated with the symptomatology and pathogenesis of sepsis in both experimental models 41,42 and human clinical studies 43–45 .…”

Signaling by IL-6 promotes alternative activation of macrophages to limit endotoxemia and obesity-associated resistance to insulin

“…Whole blood was collected into heparinized tubes 6 hours post injection, and spun at 7000 g (4° C) for 7 minutes to obtain plasma. LPS serotype and preparation as well as administration route, were chosen based on previous publications 44,45 . Levels of cytokines were quantified in plasma (diluted 1:2) using Multiplex Bead Immunoassays (Life Technologies, CA) and a Bio-Plex 200 system (Bio-Rad, UK) according to the manufacturer’s instructions.…”