The central role of hypothalamic inflammation in the acute illness response and cachexia

Abstract

When challenged with a variety of inflammatory threats, multiple systems across the body undergo physiological responses to promote defense and survival. The constellation of fever, anorexia, and fatigue is known as the acute illness response, and represents an adaptive behavioral and physiological reaction to stimuli such as infection. On the other end of the spectrum, cachexia is a deadly and clinically challenging syndrome involving anorexia, fatigue, and muscle wasting. Both of these processes are governed by inflammatory mediators including cytokines, chemokines, and immune cells. Though the effects of cachexia can be partially explained by direct effects of disease processes on wasting tissues, a growing body of evidence shows the central nervous system (CNS) also plays an essential mechanistic role in cachexia. In the context of inflammatory stress, the hypothalamus integrates signals from peripheral systems, which it translates into neuroendocrine perturbations, altered neuronal signaling, and global metabolic derangements. Therefore, we will discuss how hypothalamic inflammation is an essential driver of both the acute illness response and cachexia, and why this organ is uniquely equipped to generate and maintain chronic inflammation. First, we will focus on the role of the hypothalamus in acute responses to dietary and infectious stimuli. Next, we will discuss the role of cytokines in driving homeostatic disequilibrium, resulting in muscle wasting, anorexia, and weight loss. Finally, we will address mechanisms and mediators of chronic hypothalamic inflammation, including endothelial cells, chemokines, and peripheral leukocytes.

Establishment and characterization of a novel murine model of pancreatic cancer cachexia

“…A large body of evidence demonstrates that the hypothalamus is a critical driver of cachexia, transducing systemic inflammatory messages stemming from acute and chronic disease processes into a local and paracrine inflammatory response in the central nervous system 23, 24, 25. Consistent with this evidence, KPC induces an array of genes responsive to inflammatory stimuli in the hypothalamus.…”

Respiratory Syncytial Virus (RSV) Pulmonary Infection in Humanized Mice Induces Human Anti-RSV Immune Responses and Pathology

“…Therefore, the HIS mice could productively clear the RSV infection, while the infection persisted in the immunodeficient NSG mice. The immune cell-mediated induction of cytokines in response to a pathogen is primarily responsible for the feeling of sickness and the loss of body weight (39,40). Correspondingly, the robust human cellderived cytokine response to RSV in HIS mice is likely responsible for the observed loss of body weight.…”

Animal models of cardiac cachexia

“…The hypothalamus-pituitary gland axis regulates glucocorticoid release [18] which promotes catabolism in peripheral tissues [19] among which skeletal muscle. When the inflammation persists, this mobilization of protein from skeletal muscle leads to atrophy [20]. Moreover, in the context of subacute and chronic disease, the persistent inflammation determines also the onset of hypothalamic inflammation (responsible for the regulation of appetite, body mass and energy homeostasis) and the transition from sickness to cachexia [21].…”