Differential modulation of bacteria-induced sickness and inflammation by double stranded RNA-dependent protein kinase (PKR)

Abstract

Sickness refers to a set of adaptive, physiological (e.g. fever) and behavioral (e.g. malaise, anorexia, social withdrawal, and fatigue) changes in response to systemic inflammatory insults, e.g. infection and injury. While these responses collectively serve to facilitate an organism to recover, increasing lines of evidence indicate that sickness, if exacerbated, may precipitate depression and delirium. Hence, it will be beneficial to discover suitable approaches to modulate sickness so as to maximize its benefits and minimize its side effects. As double-stranded RNA-dependent protein kinase (PKR) is key kinase regulating inflammation, the aim of this study is to investigate whether PKR also plays a regulatory role in sickness. PKR+/+ and PKR-/- mice were infected subcutaneously with live Escherichia coli (E. coli.) or vehicle. Sickness was assessed by monitoring fever, food consumption, burrowing, and open field activity for five days. Moreover, the brain and the liver were collected for quantitative polymerase chain reaction (qPCR) of the inflammatory markers interleukin-1β (IL-1β) and cyclooxygenase (COX-2).After being challenged by E. coli., PKR-/- mice developed prolonged fever (2-3 days) as compared to PKR+/+ mice (3-4 days). Moreover, PKR-/- mice showed greater hypophagia during the early phase of sickness (day 1-2), which was followed a more pronounced hyperphagia in the late phase of sickness (day 4-5). While both types of mice displayed similar decreases of burrowing activities, PKR-/- mice exhibited a greater reduction in open field activity than PKR+/+ mice. Furthermore, IL-1ß and COX2 in PKR +/+ and PKR-/- mice were differentially expressed in the brain and the liver following E. coli. challenge.It has been known that PKR participates in up-regulating inflammatory responses in immune cells, and that inflammatory factors such as IL-1β and COX-2 are key players in causing sickness during systemic inflammation. Our data is consistent with the literature that deficiency of PKR could lower the expression of systemic inflammatory markers after immune challenge. These findings shall (1) shed light on the suitability of PKR as a target to modulate sickness, and (2) stimulate us to refine the current concepts relating infection, systemic inflammation, and sickness.