Abstract
Upon pathogen infection, microbial killing pathways and cellular stress pathways are rapidly activated by the host innate immune system. These pathways must be tightly regulated because insufficient or excessive immune responses have deleterious consequences. Increasing evidence indicates that the nervous system regulates the immune system to confer coordinated protection to the host. However, the precise mechanisms of neural-immune communication remain unclear. Previously we have demonstrated that OCTR-1, a neuronal G protein-coupled receptor, functions in the sensory neurons ASH and ASI to suppress innate immune responses in non-neural tissues against Pseudomonas aeruginosa in Caenorhabditis elegans. In the current study, by using a mass spectrometry-based quantitative proteomics approach, we discovered that OCTR-1 regulates innate immunity by suppressing translation and the unfolded protein response (UPR) pathways at the protein level. Functional assays revealed that OCTR-1 inhibits specific protein synthesis factors such as ribosomal protein RPS-1 and translation initiation factor EIF-3.J to reduce infection-triggered protein synthesis and UPR. Translational inhibition by chemicals abolishes the OCTR-1-controlled innate immune responses, indicating that activation of the OCTR-1 pathway is dependent on translation upregulation such as that induced by pathogen infection. Because OCTR-1 downregulates protein translation activities, the OCTR-1 pathway could function to suppress excessive responses to infection or to restore protein homeostasis after infection.
Highlights
As sepsis, autoimmune disease and chronic inflammatory disease
We examine how C. elegans responds to P. aeruginosa infection and how the nervous system regulates those responses at the protein level
To investigate how C. elegans responds to P. aeruginosa infection at the protein level, we compared the proteomes of infected wild-type N2 worms to those of uninfected controls using a label-free quantitative proteomics approach
Summary
As sepsis, autoimmune disease and chronic inflammatory disease. Increasing evidence indicates that the nervous system regulates the immune system to confer coordinated protection to the host[13,14,15]. C. elegans deficient in NPR-1, a homologue of the neuropeptide Y receptor in mammals, shows decreased innate immune responses to infections by Pseudomonas aeruginosa, Salmonella enterica or Enterococcus faecalis but enhanced immune defense against Bacillus thuringiensis[16,19] This suggests that the NPR-1-expressing neurons regulate innate immunity to certain pathogens. We have demonstrated that loss of expression of OCTR-1, a putative catecholamine GPCR, in the nematode’s sensory ASH and ASI neurons increases innate immune responses to P. aeruginosa, indicating that OCTR-1 functions in ASHs and ASIs to suppress innate immunity[17,18] This regulation is partially achieved by down-regulating gene expression of the p38 MAPK pathway and the UPR pathways in pharyngeal and intestinal tissues that are the primary line of defense against microbial pathogens. We examine how C. elegans responds to P. aeruginosa infection and how the nervous system regulates those responses at the protein level
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