Journal of Molecular Biology
ReviewAnimal Models for the Study of Nucleic Acid Immunity: Novel Tools and New Perspectives
Graphical Abstract
Introduction
Dysregulations of inflammatory responses underlie a wide range of human pathologies, including cancer, infectious or autoimmune disorders. “Inflammation” is operationally described as the physical manifestations of a local immune response to injury or infections, including tissue swelling, pain, redness and elevated temperature. These symptoms result from cell-mediated responses to either invading pathogens or local injuries after detection of damage-associated molecular patterns. This localized response, when controlled, is beneficial because it facilitates the recruitment of effector cells and enhances their circulation toward lymph nodes, activating the adaptive immune system.
Under physiological conditions, this process is self-limiting and inflammation is resolved as the infection is cleared or the injury repaired. The correct orchestration of the steps composing these cellular and humoral responses, from its initiation to its resolution, is therefore crucial to restore homeostasis. Indeed, chronic unresolved inflammation causes cell and tissue damage while potentially impacting hematopoiesis and causing hematological disorders [1]. Common symptoms of chronic inflammation include fatigue, discomfort, pain and weight loss. However, specific additional symptoms may arise, depending on the condition associated with, or resulting from, chronic inflammation such as joint pain and a limited range of motion experienced by rheumatoid arthritis patients. In addition, chronic inflammation triggered by autoimmune diseases or by modern diet and lifestyle is associated with cardiovascular, muscular, bone and neurodegenerative diseases as well as cancer [2]. In most cases, it is, however, difficult to comprehend whether chronic inflammation is the cause or consequence of a specific pathology.
Research performed during the past decades shows that nucleic acid sensing defects are frequently associated with the onset of chronic disease-promoting, or disease-promoted, inflammatory signaling. The first evidence for the induction of nucleic acid-promoted cytokine production dates from the early 1960s [3]. Double-stranded RNA and poly(I:C) were shown to induce the production of type I interferon (IFN), a potent antiviral cytokine. It took several decades for the immune-stimulatory nature of DNA to be demonstrated [4]. An even more recent notion is the immune-stimulatory potential of endogenous, mitochondrial or nucleus-derived, nucleic acid species [5].
Since then, the presence of endogenous inflammatory nucleic acids, including ssDNA, dsDNA and RNA:DNA hybrids, has been associated with several chronic inflammatory pathologies [6]. Despite the multifactorial origin of the nucleic acid accumulation, it induces a common dysregulation of cytokine production that culminates in chronic inflammation [7]. Genetic disorders, persistent infections and cancers have thus been related to inflammatory diseases resulting from nucleic acids accumulation [8].
Cytosolic nucleic acid detection pathways have been vastly explored in vitro (in immune and non-immune cell types) and in vivo, mostly focusing on murine models. However, recent work underscores the existence of cell-type-dependent and species-specific detection mechanisms, urging for re-evaluation of nucleic acid sensing in regard to both the spatial distribution of nucleic acid sensors (subcellular, cell and tissue localization) and the evaluation of crosstalk between co-existing signaling pathways. Herein, we summarize the current challenges in the nucleic acid immunity field, focusing on the cGAS-STING pathway, involved in the detection of cytosolic self and non-self dsDNA. In this light, we will discuss the complementarity and limits of murine and zebrafish models for the study of nucleic acid-mediated inflammatory responses and the development of high-content therapeutic screening strategies. Comparative analyses of the species specificities have allowed the identification of therapeutic targets conserved between human, mouse and zebrafish models [9] and facilitated the development of drug screening approaches to treat inflammatory pathologies of different origins. Zebrafish model present advantages (optical transparency of the embryos, small size and high conservation of human genes) that can be exploited to promote the development of cost-effective therapeutic screening approaches. However, this model faces several limitations such as differences in adaptive immunity, lack of inbred strains and the duplication of its genome (human genes can have multiple copies in zebrafish genome) [10]. These parameters are crucial to take into account and underscore that zebrafish rather complement existing murine models. Furthermore, in vivo animal models have recently been challenged by organoid cultures that provide perspectives in the development of precision medicine. This will be discussed, alongside other recent breakthrough technical approaches may open new perspective in the monitoring of regionalized immune responses.
Section snippets
Type I IFN production in health and disease
IFNs belong to the class II helical cytokine family of signaling molecules, encoded by an intron-less multigene family. In humans, the type I IFN family includes at least 13 IFNα, in addition to IFNβ, IFNε, IFNκ, IFNω. They all signal through binding to the virtually ubiquitous heterodimeric interferon-α/β receptor (IFNAR) [11]. In the mouse genome, 14 IFNα and single IFNβ, IFNε and IFNκ genes have been identified. Murine Limitin (also known as IFN ζ) was not found in the human genome, while no
Cytosolic dsDNA and IFN-Related Disorders: Emerging Challenges
Most of our current understanding of nucleic acid detection pathways comes from studies of pathogen-associated inflammatory responses and has been improved through the emergence of models reproducing chronic inflammatory disorders. Below, we discuss some of the most used models of these pathologies to highlight the benefit of combining such divergent systems to decipher nucleic acid immunity and identify potential therapeutic targets common to different pathologies.
Future of Cytosolic NA Immunity Disorders and Therapeutic Perspectives
Altogether, the various origins of diseases linked to chronic type I IFN production, and the dichotomous impact of IFN (sometime pro-, sometimes anti-inflammatory) underscores the need for novel approaches to screen for:
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the pathways elicited upon immunological challenge.
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the impact of different stimulus in specific microenvironments.
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the discovery of novel inflammatory and anti-inflammatory compounds and assessment of their impact.
Below, we review the tools and models developed to reach these
Systems-Level Analysis of Nucleic Acid Immunity: Novel Insights and Old Concepts
Previously mentioned innovative technologies and analysis tools that generate and process Big data (omics data) have evolved at a rapid pace over recent year, projecting immunology research into systems-level analysis of immune responses [110].
Systems analysis aims to the integrate information emerging from several hierarchical levels (from cells to organisms or from molecules to tissues) and take into account the physiological context: cellular diversity, inter-cellular communications, tissues
Conflicts of Interest
The authors declare no conflict of interest.
Author Contributions
I.K.V., M.F., D.V., N.L, and C.L. drafted and edited the manuscript.
Funding
The research leading to these was partly funded by the EU INFRAIA project VetBioNet (EU H2020 project 731014) and received institutional support from INRAE. The INRAE Infectiology of Fishes and Rodents Facility (IERP-UE907 DOI: 10.15454/1.5572427140471238E12, Jouy-en-Josas Research Center, France) belongs to the National Distributed Research Infrastructure for the Control of Animal and Zoonotic Emerging Infectious Diseases through In Vivo Investigation (EMERG'IN DOI: //dx.doi.org/10.15454/1.5572352821559333E12
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Cited by (0)
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N.L. and C.L. contributed equally this work.