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Constitutive immune mechanisms: mediators of host defence and immune regulation

Nature Reviews Immunology volume 21, pages 137–150 (2021)Cite this article

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Abstract

The immune system enables organisms to combat infections and to eliminate endogenous challenges. Immune responses can be evoked through diverse inducible pathways. However, various constitutive mechanisms are also required for immunocompetence. The inducible responses of pattern recognition receptors of the innate immune system and antigen-specific receptors of the adaptive immune system are highly effective, but they also have the potential to cause extensive immunopathology and tissue damage, as seen in many infectious and autoinflammatory diseases. By contrast, constitutive innate immune mechanisms, including restriction factors, basal autophagy and proteasomal degradation, tend to limit immune responses, with loss-of-function mutations in these pathways leading to inflammation. Although they function through a broad and heterogeneous set of mechanisms, the constitutive immune responses all function as early barriers to infection and aim to minimize any disruption of homeostasis. Supported by recent human and mouse data, in this Review we compare and contrast the inducible and constitutive mechanisms of immunosurveillance.

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Fig. 1: Constitutive innate immune responses versus inducible immune responses.
Fig. 2: Constitutive innate immune responses negatively regulate inducible immune responses.
Fig. 3: Overview of the regulation of microbial replication by constitutive innate immune mechanisms.
Fig. 4: Constitutive control of microbial replication by restriction factors and autophagy.

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Acknowledgements

S.R.P. is funded by the European Research Council (ERC-AdG ENVISION; 786602), the Novo Nordisk Foundation (NNF18OC0030274) and the Lundbeck Foundation (R198-2015-171 and R268-2016-3927). T.P. is funded by the European Research Council (ERC-StG IDEM; 637647). S.L.M. acknowledges funding from a Howard Hughes Medical Institute–Wellcome International Research Scholarship and the Sylvia and Charles Viertel Foundation. T.H.M. received funding from Aarhus University Research Foundation (AUFF-E-215-FLS-8-66), the Danish Council for Independent Research-Medical Sciences (4004-00047B) and the Lundbeck Foundation (R268-2016-3927). The authors thank D. Olagnier for critical reading of the manuscript and comments and suggestions.

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Authors and Affiliations

  1. Department of Biomedicine, Aarhus University, Aarhus, Denmark

    Søren R. Paludan & Trine H. Mogensen

  2. Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden

    Søren R. Paludan

  3. CNRS UMR 5164 ImmunoConcept, University of Bordeaux, Bordeaux, France

    Thomas Pradeu

  4. Department of Biological and Medical Sciences, University of Bordeaux, Bordeaux, France

    Thomas Pradeu

  5. Inflammation Division, The Walter and Eliza Hall Institute, Melbourne, VIC, Australia

    Seth L. Masters

  6. Department of Medical Biology, The University of Melbourne, Melbourne, VIC, Australia

    Seth L. Masters

  7. Department of Clinical Medicine, Aarhus University, Aarhus, Denmark

    Trine H. Mogensen

  8. Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark

    Trine H. Mogensen

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S.R.P. conceived the idea and wrote the first version of the manuscript together with T.H.M. All authors together fully developed the work, and drafted, finalized and revised the manuscript.

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Glossary

Pattern recognition receptors

(PRRs). A family of germline-encoded immune receptors, including the Toll-like receptors, that detect immunostimulatory molecules to activate signal transduction and gene expression, which induces antimicrobial and inflammatory responses.

Constitutive immune mechanisms

Host mechanisms that are constitutively present in an active or latent form and thus can exert host defence activities immediately, independently of inducible processes.

Inducible mechanisms

Biological processes that depend on the activation of transcriptional programmes and hence require intermediate steps between the trigger stimulus and effector function.

Supramolecular organizing centres

Location-specific higher-order signalling complexes, such as the myddosome in Toll-like receptor signalling, that amplify pattern recognition receptor signalling when pathogen-associated molecular pattern levels exceed specific threshold concentrations.

RNA interference

(RNAi). The use of double-stranded RNA molecules containing sequences that match a given gene to knock down the expression of that gene by inhibiting translation of the targeted mRNA or by directing RNA-degrading enzymes to destroy the encoded mRNA transcript.

Nuclear domain 10 bodies

(ND10 bodies). Membraneless, interchromatin structures in the nucleus of eukaryotic cells. ND10 bodies are made up mainly of proteins and have been described to be involved in a broad range of processes, including gene regulation, cell cycle, apoptosis, DNA repair and antiviral defence.

Aerobic glycolysis

The process by which glucose is converted to lactate in the presence of oxygen to produce energy in the form of ATP.

cGAS–STING pathway

(Cyclic GMP–AMP synthase–stimulator of interferon genes pathway). cGAS is a cytosolic DNA-sensing pattern recognition receptor that signals via STING to induce the expression of type I interferon and inflammatory cytokines.

RIG-I–MAVS pathway

(Retinoic acid-inducible gene I protein–mitochondrial antiviral signalling protein pathway). RIG-I is a cytosolic RNA-sensing pattern recognition receptor that signals via MAVS to induce the expression of type I interferon and inflammatory cytokines.

DNA damage response

Cellular response to DNA damage, including the re-establishment of genome integrity and cell death responses.

NLRP3 inflammasome

The NLRP3 inflammasome is activated by danger-associated molecular patterns and molecular signatures associated with homeostasis-altering molecular processes to execute caspase 1-mediated cleavage of molecules such as pro-IL-1β and gasdermin D.

NRF2–KEAP1

Nuclear factor erythroid 2-related factor 2 (NRF2) senses oxidative stress, whereupon it is released from Kelch-like ECH-associated protein 1 (KEAP1) to translocate to the nucleus and induce gene expression.

Hypoxia-inducible factor 1α

A transcription factor that is activated by hypoxia to induce the expression of genes with hypoxia-responsive elements in their promoters.

Bone morphogenetic protein–SMAD

Bone morphogenetic proteins are growth factors that signal through SMAD proteins to induce gene transcription.

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Paludan, S.R., Pradeu, T., Masters, S.L. et al. Constitutive immune mechanisms: mediators of host defence and immune regulation. Nat Rev Immunol 21, 137–150 (2021). https://doi.org/10.1038/s41577-020-0391-5

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