The induction of type I interferons (IFNs) is the first line of defense against pathogens encountered by the body. From a research standpoint, the chief role of these cytokines is as qualitative and quantitative beacons of both innate and adaptive immune responses. In addition, there are several diseases for which IFN is utilized as a therapy, and many more that have pathology caused by activation of IFN and induction of the downstream genes regulated by these cytokines. Given their increasing prevalence worldwide, the need for new and more effective therapies for autoimmune and inflammatory diseases is apparent.
Mouse model systems of several autoimmune and inflammatory diseases are well-established and have been successfully employed to elucidate disease pathology as well as to evaluate the efficacy of therapeutic approaches. For most diseases, both spontaneously arising and induced mouse models are actively employed in research. Spontaneous models result from alterations to an animal's genetics, whereas induced animal models are generated through exposure to chemicals or antigens.
The importance of using mouse models to study IFN-associated diseases is highlighted by the fact that several therapeutic approaches first evaluated in animal models have progressed to clinical trials and have subsequently gained approval for human use. For example, IFN-beta administration is the standard of care for treatment of many multiple sclerosis (MS) patients [1]. However, the exact mechanism of action of IFN in this disease remains unclear. Thus, the role of IFN-beta in both the inhibition and pathogenesis of autoimmunity remains an area of much interest. Moreover, due to the side effects and difficulty administering IFN therapies, novel formulations of these therapies are continually being developed and tested in animal models prior to entering clinical trials.
Recent advances in mathematical modeling and systems biology approaches have further enhanced the translational potential of these models, enabling more precise prediction of therapeutic efficacy in human diseases [2].
Mouse Models of Multiple Sclerosis (MS)
Multiple Sclerosis (MS) is a debilitating autoimmune disease that affects the central nervous system. Long after the value of IFN-beta as a therapeutic in the treatment of MS was recognized, the role of the Th17 subset of cells, and subsequently a major mechanism of action for IFN-beta, was demonstrated in the experimental autoimmune encephalitis (EAE) mouse model of MS [3]. EAE is induced when mice are immunized with myelin, myelin components, or related synthetic peptides. Mice lacking the type I IFN receptor have been shown to develop more severe EAE, and IFN-beta has been shown to specifically inhibit human Th17 cell differentiation [3,4]. More recently, this effect has been shown to be mediated through the regulation of dendritic cell (DC) activation and migration by IFN-beta. This is key due to the role of DCs as drivers of the pathogenic Th17 cell response in this disease [5].
Recent developments in EAE research have focused on understanding B cell contributions to IFN-β therapy efficacy. Studies have demonstrated that IFN-β treatment skews B cells towards a regulatory phenotype, and B cell function significantly impacts therapeutic outcomes in EAE models [6]. Additionally, novel therapeutic approaches including mesenchymal stem cell (MSC) therapy have shown promising immunomodulatory and neuroprotective effects in EAE, with MSCs demonstrating anti-proliferative, anti-inflammatory, and anti-apoptotic effects on neurons [7].
A groundbreaking development has been the creation of noninflammatory mRNA vaccines for EAE treatment, which induce antigen-specific tolerance without triggering inflammatory responses [8]. This represents a significant advancement in precision medicine approaches to autoimmune diseases.
While EAE is the most commonly used model, it does have limitations. Therefore, some researchers use either toxin or virus-induced demyelination, such as infection of mice with Theiler's mouse encephalomyelitis virus (TMEV) as a model system for MS. Intracerebral injection of TMEV, a single-stranded, positive polarity RNA picornavirus, results in an acute infection followed by chronic demyelination and MS-like pathologies [9]. While these models do not recapitulate all clinical and pathological features of MS, their utility has been substantiated through their use in the generation of several approved therapeutics.
Mouse Models of Lupus
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by autoantibody production, lymphoid activation and hyperplasia, and lupus nephritis [10]. A hallmark of SLE is the overproduction of type I IFNs and a strong interferon response gene signature. In fact, the relatively recently coined term interferonopathy is often used to refer to SLE. Interferonopathies are a group of Mendelian disorders believed to be caused by mutations in DNA-sensing and proteasome machinery. While it remains to be proven that type I interferon is causative of these diseases, there is a correlation between overproduction of this cytokine and the onset of these disorders [11].
Mouse SLE research focuses predominantly on several key spontaneous and induced mouse models. Frequently used spontaneous models include the NZB/W F1 mouse, which is an F1 hybrid between the New Zealand Black (NZB) and New Zealand White (NZW) strains; the MRL/lpr; and the BXSB/Yaa strains. Recent research has revealed that the male bias in BXSB mice is attributable to the Y-autoimmune accelerator (Yaa) locus, which arose from an X to Y chromosome translocation, doubling the genomic copy number and expression of several key genes [12].
Induced SLE models include the pristane-induced model and the chronic graft-versus-host-disease (cGVHD) models. Recent advances in pristane-induced lupus models have shown significant promise for studying neuropsychiatric lupus (NPSLE). Pristane-induced lupus (PIL) mice exhibit characteristic behavioral deficits including olfactory dysfunction, anxiety, and depression-like phenotype, along with elevated cytokine levels (IL-1β, IFN-α, IFN-β, IL-10, IFN-γ, IL-6, TNF-α, and IL-17A) and chemokines (CCL2 and CXCL10) in the brain [13]. Furthermore, pristane treatment in SNF1 mice has been shown to recapitulate kidney disease parameters and molecular signatures seen in spontaneous models, providing an accelerated model for studying lupus nephritis [14].
A significant advancement has been the development of humanized mouse models of SLE. Injection of pristane into immunodeficient mice reconstituted with human immune systems successfully recapitulates key SLE features, including production of human anti-nuclear autoantibodies, lupus nephritis, and pulmonary serositis, while mimicking the lymphopenia observed in human patients [15].
Each of these models share some pathophysiology with the human disease, and research into the unique genetics of the spontaneous mouse models has led to many important discoveries. In addition, clinical IFN administration used for the treatment of other diseases has been reported to cause lupus-like symptoms and autoantibody overproduction in a subpopulation of patients [12].
Collagen-Induced Arthritis Mouse Model of Rheumatoid Arthritis
Rheumatoid arthritis (RA) is a chronic inflammatory condition that causes inflammation and thickening of synovial fluid in joints. Among several models of this disease, immunization of DBA/1 mice with type II collagen in complete Freund's adjuvant is prevalently used, as it results in erosive polyarthritis and an autoimmune response against cartilage. Collagen-induced arthritis (CIA) has been applied to several gene-knockout mice in order to determine which genes might be involved in this autoimmune disease [16]. As a result, important roles for certain class II MHC haplotypes as well as PTPN22, a tyrosine phosphatase, have been identified in some patient populations. Furthermore, the importance of IFN-gamma in the pathogenesis of RA has been suggested by studies of CIA in mice deficient for the IFN-gamma receptor [17]. Passive immunization models of RA include collagen antibody-induced arthritis and K/BxN antibody transfer arthritis.
In addition, a transgenic mouse overexpressing TNF-alpha has been utilized as a spontaneous model of RA [18]. The first line of treatment for RA consists of TNF antagonists; however, 40 to 50% of patients fail to respond to this approach. For some of these patients B cell depletion therapy using rituximab has been shown to be efficacious. Moreover, recently it has been shown that baseline interferon response gene levels can be a predictive biomarker for non-response to rituximab [19]. Current research trends for 2025 indicate expanding applications of B cell-depletion therapy in certain subsets of the autoimmune population, representing a growing therapeutic approach [20].
Mouse Models of Asthma
Asthma is defined as chronic inflammation of the airways and is generally thought to occur in response to constant or intermittent exposure to antigens. T helper type 2 (Th2) cells are key mediators of the immunopathology of asthma. Huber et al discovered a role for type I IFNs in the inhibition of human Th2 cell development, indicating a potential additional therapeutic application for this cytokine [21]. The precise cellular and molecular mechanisms underlying the inflammation and tissue changes in asthma remain undefined. However, several mouse models based on aerosolized exposure to an antigen, often derived from the ovalbumin peptide, have been developed and are currently in use to study airway hyper-responsiveness. While these acute challenge models reproduce many of the clinical features of asthma, the pattern and distribution of pulmonary inflammation is different than that seen in human disease [22]. Kumar et al recently suggested that most mouse asthma models represent potentiation of chronic asthma rather than acute exacerbations, which are the most cause of healthcare visits and hospitalizations [23]. In humans respiratory viral infections are believed to cause the majority of acute asthma exacerbations.
Inflammatory Bowel Disease (IBD)
Inflammatory bowel diseases (IBD), including Crohn's and colitis, are caused by dysregulation of inflammatory mediators resulting in an imbalance in gut innate and adaptive innate immune responses. Although they have similar etiologies, the pathogenesis of Crohn's and ulcerative colitis are markedly distinct. Crohn's disease is a chronic inflammatory bowel disease characterized most frequently in humans by inflammation of the terminal ileum, although it can affect any of the gastrointestinal tract. In contrast, colitis affects only the inner most layer of the colon.
It is hypothesized that these diseases are a consequence of breakdown in intestinal barrier function, resulting in exposure of microbial antigens to the immune system. An association between mutations in the Nod2 gene in humans and onset of Crohn's disease has been discovered. Nod2 is an activator of innate immune responses including production of IFN-beta, thus highlighting the potential utility of this cytokine as a downstream readout in Crohn's disease. Moreover, recent studies have supported the role of dysregulation of the type I IFN response in IBD [24]. A variety of chemically- and genetically-induced mouse models of this disease have been utilized, as well as spontaneous models of chronic ileal inflammation [25]. The most common chemical inducers of IBD are 2,4,6-trinitrobenzenesulfonic acid (TNBS), dextran sodium sulfate (DSS), and oxazolone [26,27].
Type I Diabetes
One of the most famous mouse research models, the non-obese diabetic (NOD) strain of mice, was first isolated in the early 1980s [28]. This strain harbors multiple genetic mutations that result in the development of diabetes with 100% penetrance. While the role of IFN in this autoimmune disease is still under investigation, findings point to type I IFNs as initiators of type 1 diabetes in the NOD mouse [29]. Further, type 1 diabetes is considered an interferonopathy as it has been found that expression of interferon-inducible genes correlate with its onset [30]. Recent research has identified that more than 20 chromosomal regions, defined as genetic intervals influencing susceptibility to diabetes (Idd), contribute to the development of T1D in NOD mice. The NOD mouse model has also proven valuable for studying Sjögren's syndrome, as it serves as the most extensively studied animal model for both human T1D and SjS [31].
The utility of the NOD mouse model in the study of type I diabetes is exemplified by its continued use, as well as the transfer of therapies derived from studies in this mouse to human clinical trials. Similarities between the NOD mouse and human disease include the development of spontaneous autoimmune disease, pancreas-specific autoantibodies, accumulation of autoreactive T cells, and synteny with human disease [32]. Further study of the role of IFN in this disease is clearly indicated.
Emerging Areas and Novel Findings
Recent research has identified RSAD2 as a pathogenic interferon-stimulated gene at the maternal-fetal interface in patients with systemic lupus erythematosus. Studies in pregnant mouse models exposed to type I interferon inducers have shown that depletion of Rsad2 significantly reduces lipid accumulation, vascular injury, and embryo development disorders, with the RSAD2 inhibitor L-chicoric acid (LCA) showing therapeutic potential [33].
Additionally, advances in understanding type I interferon signaling have been enhanced through studies of SARS-CoV-2 mouse models, which have revealed the inflammatory role of type I interferon signaling in viral infections, providing insights that may be applicable to autoimmune interferonopathies [34].
Summary
Immense contributions have been made to the fields of autoimmune and infectious diseases as a result of the analysis of animal models. While it is not always possible to extrapolate mouse-based results into human clinical settings, the utility of animal models as a first approach to both study the basic biology of diseases and to test potential therapeutics continues to be an important part of life science research and drug discovery process. Recent advances in mathematical modeling, systems biology approaches, and humanized mouse models have significantly enhanced the translational potential of these research tools [2,15]. As additional model systems and more efficient downstream measures of autoimmunity become available, insight into the precipitating causes of autoimmunity, as well as potential therapeutic interventions, can be rapidly uncovered. Accurate quantitation of IFNs as a measure between healthy and disease state will allow further understanding of their roles in these diseases, and may lead to better treatment efficacy.
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