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Background  The cellular prion protein (PrP C ) is an evolutionary conserved protein abundantly expressed not only in the central nervous system but also peripherally including the immune system. A line of Norwegian dairy goats naturally devoid of PrP C  ( PRNP   Ter/Ter ) provides a novel model for studying PrP C  physiology.    Methods  In order to explore putative roles for PrP C  in acute inflammatory responses, we performed a lipopolysaccharide (LPS,  Escherichia coli  O26:B6) challenge of 16 goats (8  PRNP   +/+  and 8  PRNP   Ter/Ter ) and included 10 saline-treated controls (5 of each  PRNP  genotype). Clinical examinations were performed continuously, and blood samples were collected throughout the trial. Genome-wide transcription profiles of the choroid plexus, which is at the blood-brain interface, and the hippocampus were analyzed by RNA sequencing, and the same tissues were histologically evaluated.    Results  All LPS-treated goats displayed clinical signs of sickness behavior, which were of significantly ( p  < 0.01) longer duration in animals without PrP C . In the choroid plexus, a substantial alteration of the transcriptome and activation of Iba1-positive cells were observed. This response included genotype-dependent differential expression of several genes associated with the immune response, such as  ISG15 ,  CXCL12 ,  CXCL14 , and acute phase proteins, among others. Activation of cytokine-responsive genes was skewed towards a more profound type I interferon response, and a less obvious type II response, in PrP C -deficient goats. The magnitude of gene expression in response to LPS was smaller in the hippocampus than in the choroid plexus. Resting state expression profiles revealed a few differences between the  PRNP  genotypes.    Conclusions  Our data suggest that PrP C  acts as a modulator of certain pathways of innate immunity signaling, particularly downstream of interferons, and probably contributes to protection of vulnerable tissues against inflammatory damage.    Electronic supplementary material  The online version of this article (doi:10.1186/s12974-017-0879-5) contains supplementary material, which is available to authorized users.

LPS-induced systemic inflammation reveals an immunomodulatory role for the prion protein at the blood-brain interface