气候变化领域集成服务门户(CCPortal): PACAP is a pathogen-inducible resident antimicrobial neuropeptide affording rapid and contextual molecular host defense of the brain

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DOI	10.1073/PNAS.1917623117
	PACAP is a pathogen-inducible resident antimicrobial neuropeptide affording rapid and contextual molecular host defense of the brain
	Lee E.Y.; Chan L.C.; Wang H.; Lieng J.; Hung M.; Srinivasan Y.; Wang J.; Waschek J.A.; Ferguson A.L.; Lee K.-F.; Yount N.Y.; Yeaman M.R.; Wong G.C.L.
发表日期	2021
ISSN	00278424
卷号	118 期号:1
英文摘要	Defense of the central nervous system (CNS) against infection must be accomplished without generation of potentially injurious immune cell-mediated or off-target inflammation which could impair key functions. As the CNS is an immune-privileged compartment, inducible innate defense mechanisms endogenous to the CNS likely play an essential role in this regard. Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide known to regulate neurodevelopment, emotion, and certain stress responses. While PACAP is known to interact with the immune system, its significance in direct defense of brain or other tissues is not established. Here, we show that our machine-learning classifier can screen for immune activity in neuropeptides, and correctly identified PACAP as an antimicrobial neuropeptide in agreement with previous experimental work. Furthermore, synchrotron X-ray scattering, antimicrobial assays, and mechanistic fingerprinting provided precise insights into how PACAP exerts antimicrobial activities vs. pathogens via multiple and synergistic mechanisms, including dysregulation of membrane integrity and energetics and activation of cell death pathways. Importantly, resident PACAP is selectively induced up to 50-fold in the brain in mouse models of Staphylococcus aureus or Candida albicans infection in vivo, without inducing immune cell infiltration. We show differential PACAP induction even in various tissues outside the CNS, and how these observed patterns of induction are consistent with the antimicrobial efficacy of PACAP measured in conditions simulating specific physiologic contexts of those tissues. Phylogenetic analysis of PACAP revealed close conservation of predicted antimicrobial properties spanning primitive invertebrates to modern mammals. Together, these findings substantiate our hypothesis that PACAP is an ancient neuro-endocrine-immune effector that defends the CNS against infection while minimizing potentially injurious neuroinflammation. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	Antimicrobial peptides; Host defense; Innate immunity; Neuroimmunology; Neuropeptides
语种	英语
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/181122
作者单位	Department of Bioengineering, University of California, Los Angeles, CA 90095, United States; UCLA-Caltech Medical Scientist Training Program, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, United States; Lundquist Institute for Biomedical Innovation, Harbor-UCLA Medical Center, Torrance, CA 90509, United States; Division of Molecular Medicine, Los Angeles County, Harbor-UCLA Medical Center, Torrance, CA 90509, United States; Division of Infectious Diseases, Los Angeles County, Harbor-UCLA Medical Center, Torrance, CA 90509, United States; Semel Institute for Neuroscience and Human Behavior, Intellectual Development and Disabilities Research Center, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, United States; Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL 60637, United States; Peptide Biology Laboratories, Salk Institute for Biological Studies, San diego, CA 92037, United States; Department of Medicine, David Geffen...
推荐引用方式 GB/T 7714	Lee E.Y.,Chan L.C.,Wang H.,et al. PACAP is a pathogen-inducible resident antimicrobial neuropeptide affording rapid and contextual molecular host defense of the brain[J],2021,118(1).
APA	Lee E.Y..,Chan L.C..,Wang H..,Lieng J..,Hung M..,...&Wong G.C.L..(2021).PACAP is a pathogen-inducible resident antimicrobial neuropeptide affording rapid and contextual molecular host defense of the brain.Proceedings of the National Academy of Sciences of the United States of America,118(1).
MLA	Lee E.Y.,et al."PACAP is a pathogen-inducible resident antimicrobial neuropeptide affording rapid and contextual molecular host defense of the brain".Proceedings of the National Academy of Sciences of the United States of America 118.1(2021).