Abstract
In response to pathogen infection, the host innate immune system activates microbial killing pathways and cellular stress pathways that need to be balanced because insufficient or excessive immune responses have deleterious consequences. Recent studies demonstrate that two G protein-coupled receptors (GPCRs) in the nervous system of Caenorhabditis elegans control immune homeostasis. To investigate further how GPCR signaling controls immune homeostasis at the organismal level, we studied arrestin-1 (ARR-1), which is the only GPCR adaptor protein in C. elegans. The results indicate that ARR-1 is required for GPCR signaling in ASH, ASI, AQR, PQR, and URX neurons, which control the unfolded protein response and a p38 mitogen-activated protein kinase signaling pathway required for innate immunity. ARR-1 activity also controlled immunity through ADF chemosensory and AFD thermosensory neurons that regulate longevity. Furthermore, we found that although ARR-1 played a key role in the control of immunity by AFD thermosensory neurons, it did not control longevity through these cells. However, ARR-1 partially controlled longevity through ADF neurons.
Highlights
G protein-coupled receptors (GPCRs) function in the C. elegans nervous system to control immunity
ARR-1 Signaling Regulates Pathogen Resistance and Lifespan Extension by Targeting Different Pathways—We studied whether ARR-1 is required for C. elegans defense against bacterial infections by exposing arr-1(ok401) mutant animals to P. aeruginosa and by comparing their survival with that of wildtype animals. arr-1(ok401) animals exhibited an enhanced resistance to P. aeruginosa (ERP) phenotype (Fig. 1A), suggesting that the lack of inhibition of GPCR signaling in the entire nervous system due to a lack of ARR-1 activity enhances immunity
To determine whether the enhanced immune response caused by mutation in the arr-1 gene is specific to P. aeruginosa, we exposed arr-1(ok401) animals to S. enterica and Y. pestis, two Gram-negative pathogens known to kill C. elegans (24, 25)
Summary
GPCRs function in the C. elegans nervous system to control immunity. Results: Arrestin-1, the only GPCR adaptor in C. elegans, functions in the nervous system to control immunity. A unique advantage to the study of neural mechanisms involved in the control of immune responses in C. elegans is the unparalleled characterization of its nervous system at the cellular level. To study the role of neural GPCR signaling in the regulation of UPR genes and its role in immune defense against bacterial infections, we took advantage of a unique component of GPCR signaling, the GPCR adaptor protein arrestin-1 (ARR-1). The only member of the arrestin family in C. elegans, ARR-1, is expressed almost exclusively within the C. elegans nervous system (14), making it easy to manipulate neural ARR-1 signaling and to study its effect on innate immune responses against pathogen infection. The results highlight the importance of ARR-1 signaling in a subset of sensory neurons that control longevity and immune homeostasis during response to pathogen infection
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