Abstract
The innate immune receptor Toll-like 4 (TLR4) is the receptor activated by lipopolysaccharide (LPS), and TLR4-LPS interaction is well known to induce an innate immune response, triggering sickness behavior. Within the brain, TLR4 is highly expressed in brain microglia, and excessive inflammation resulting from activation of this pathway in the brain has been implicated in depressive disorders and neurodegenerative pathologies. We hypothesized that blocking LPS-induced activation of TLR4 would prevent downstream immune signaling in the brain and suppress the induction of sickness behavior. We used interfering peptides to block TLR4 activation and confirmed their efficacy in preventing second messenger activation and cytokine production normally induced by LPS treatment. Further, these peptides blocked morphological changes in microglia that are typically induced by LPS. We also demonstrated that intraperitoneal (i.p.) injection of Tat-TLR4 interfering peptides prevented LPS-induced sickness behavior, as assessed in home cage behavior and with the intracranial self-stimulation paradigm. These newly synthesised peptides inhibit TLR4 signaling thereby preventing changes in behavior and motivation caused by inflammatory stimuli. These peptides highlight the roll of TLR4 and microglia morphology changes in sickness behavior, and thus may be of therapeutic value in limiting the deleterious impact of excessive inflammation in specific CNS pathologies.
Highlights
Small amounts of lipopolysaccharide (LPS) from invading bacteria are one of the first signals detected by the body upon infection, and detection of LPS primes the immune system to mount a defence
Our goal was to manipulate the impact of LPS binding to TLR4 in vivo, and to impact the pathways involved in sickness behavior
Our results show a remarkable ability of two different Tat-interfering peptides to prevent the downstream actions of TLR4 receptor stimulation at the molecular, cellular and behavioral levels
Summary
Small amounts of lipopolysaccharide (LPS) from invading bacteria are one of the first signals detected by the body upon infection, and detection of LPS primes the immune system to mount a defence. Following the onset of a typical infection, individuals display a coordinated set of behavioral conditions, known collectively as sickness behavior [1,2,3], that reflect a normal acute response to inflammation. The profound changes which constitute sickness behavior include loss of motivation for food and drink, diminished social interaction, fatigue, irritability, depression and cognitive impairment [3]. The expression of sickness behavior relies on motivational reorganization of priorities, which are dependent on the biological state of the animal and can lead to diverse behavioral outcomes. The initial inflammatory response can become uncontrolled and lead to other deleterious effects including prolonged inflammation and cytokine release which is known to contribute to CNS dysfunction, chronic depressive disorders and neurodegenerative processes [2,4,5]. The CNS actions of cytokines have been implicated in sickness behavior [6,7,8], the mechanisms in the brain that trigger this behavioral response are not well understood
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
