Innate Immunity in Caenorhabditis elegans Is Regulated by Neurons Expressing NPR-1/GPCR

Abstract

A large body of evidence indicates that metazoan innate immunity is regulated by the nervous system, but the mechanisms involved in the process and the biological significance of such control remain unclear. We show that a neural circuit involving npr-1, which encodes a G-protein-coupled receptor related to mammalian neuropeptide Y receptors, functions to suppress innate immune responses. The inhibitory function of NPR-1 requires a cyclic GMP-gated ion channel encoded by tax-2 and tax-4 as well as the soluble guanylate cyclase GCY-35. Furthermore, we show that npr-1-and gcy-35-expressing sensory neurons actively suppress immune responses of non-neuronal tissues. A fullgenome microarray analysis on animals with altered neural function due to mutation in npr-1 shows an enrichment in genes that are markers of innate immune responses, including those regulated by a conserved PMK-1/P38 MAPK signaling pathway. These results present evidence that neurons directly control innate immunity in C. elegans, suggesting that G-protein coupled receptors may participate in neural circuits that receive inputs from either pathogens or infected sites and integrate them to coordinate appropriate immune responses.Innate immune defense comprises a variety of mechanisms used by metazoans to prevent microbial infections. Activation of the innate immune system upon pathogen recognition results in a rapid and definitive microbicidal response to invading microorganisms that is finetuned to prevent deleterious deficiencies or excesses in the response. The nervous system, which can respond in milliseconds to many types of nonspecific environmental stimuli, has several characteristics that make it an ideal partner with the innate immune system to regulate nonspecific host defenses (1-3). However, even though a large body of evidence indicates that metazoan innate immunity is under the control of the nervous system, the mechanisms involved in the process and the biological significance of such control remain unclear. To provide insights into the neural mechanisms that regulate innate immunity, we have taken advantage of the simple and well studied nervous and innate immune systems of Caenorhabditis elegans.The powerful genetic approaches available to C. elegans research have been used to address central questions concerning the functions of the nervous system (4). With its 302 neurons and 56 glial cells, which represent 37% of all somatic cells in a hermaphrodite, the nervous system is perhaps the most complex organ of C. elegans. Ablation of different neurons has demonstrated that sensory neurons regulate a variety of physiological processes, including dauer formation and adult lifespan (5-8). In addition, C. elegans neurons are known to express To study the role of GPCRs in the regulation of innate immune response, we first determined the susceptibility of forty C. elegans strains carrying mutations in GPCRs to the human opportunistic pathogen Pseudomonas aeruginosa strain PA14, a clinical isolate capable of rapidly killing C. elegan...

A Conserved PMK-1/p38 MAPK Is Required in Caenorhabditis elegans Tissue-specific Immune Response to Yersinia pestis Infection

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