Human in vivo neuroimaging to detect reprogramming of the cerebral immune response following repeated systemic inflammation

Gerben M Franssen,Niklas Bruse,Jan Booij,Guus P Leijte,Peter Pickkers,Matthijs Kox,Annemieke M Peters Van Ton,Mark Rijpkema,Janine Doorduin,Wilson F Abdo

doi:10.1016/j.bbi.2021.04.004

Abstract

Despite increasing evidence that immune training within the brain may affect the clinical course of neuropsychiatric diseases, data on cerebral immune tolerance are scarce. This study in healthy volunteers examined the trajectory of the immune response systemically and within the brain following repeated lipopolysaccharide (LPS) challenges. Five young males underwent experimental human endotoxemia (intravenous administration of 2 ng/kg LPS) twice with a 7-day interval. The systemic immune response was assessed by measuring plasma cytokine levels. Four positron emission tomography (PET) examinations, using the translocator protein (TSPO) ligand 18F-DPA-714, were performed in each participant, to assess brain immune cell activation prior to and 5 hours after both LPS challenges. The first LPS challenge caused a profound systemic inflammatory response and resulted in a 53% [95%CI 36–71%] increase in global cerebral 18F-DPA-714 binding (p < 0.0001). Six days after the first challenge, 18F-DPA-714 binding had returned to baseline levels (p = 0.399). While the second LPS challenge resulted in a less pronounced systemic inflammatory response (i.e. 77 ± 14% decrease in IL-6 compared to the first challenge), cerebral inflammation was not attenuated, but decreased below baseline, illustrated by a diffuse reduction of cerebral 18F-DPA-714 binding (-38% [95%CI -47 to -28%], p < 0.0001). Our findings constitute evidence for in vivo immunological reprogramming in the brain following a second inflammatory insult in healthy volunteers, which could represent a neuroprotective mechanism. These results pave the way for further studies on immunotolerance in the brain in patients with systemic inflammation-induced cerebral dysfunction.

Highlights

The discovery of innate immune cell memory shifted our under standing of innate immunity profoundly (Kurtz, 2005; Medzhitov and Janeway, 2000; Netea et al, 2011)
We demonstrate that an initial LPS challenge induced robust glial activation, reflected by diffusely increased translocator protein (TSPO) binding in the brain, in particular in cortical brain regions
The Toll-like receptor (TLR) 4 agonist LPS activates innate immune cells to release pro-inflammatory cytokines, which, among others, re sults in the recruitment of other immune cells

Summary

Introduction

The discovery of innate immune cell memory shifted our under standing of innate immunity profoundly (Kurtz, 2005; Medzhitov and Janeway, 2000; Netea et al, 2011). On one end of the spectrum, innate immune cells exposed to microbial components exhibit an enhanced pro-inflammatory phenotype following subsequent restimulation with unrelated stimuli This phenomenon was coined ‘trained immunity’ (Netea et al, 2011). On the other end of the spectrum, an initial challenge of innate immune cells with potent immunostimulants such as bacterial lipopolysaccharide (LPS) results in a severely blunted inflam matory response after restimulation with the same or a different com pound. This response is known as ‘immunotolerance’ or ‘immunoparalysis’ (Netea et al, 2016). Both trained immunity and immunotolerance may exhibit beneficial as well as detrimental conse quences for the host

Methods

Results

Conclusion