Immune-inflammatory diseases involve disruption of immune homeostasis, aberrant autoimmunity, and persistent tissue injury and include inflammatory bowel disease, rheumatoid arthritis, multiple sclerosis, and atopic dermatitis. Induced animal models reproduce key pathological processes through chemical stimulation, autoantigens, immune adjuvants, or organ injury and can be used to investigate inflammatory mechanisms and conduct in vivo intervention studies.

Keywords: immune inflammation; animal model; inflammatory bowel disease; rheumatoid arthritis; EAE; atopic dermatitis; pancreatitis; disease modeling

1 Immune-Inflammatory Diseases and Their Pathogenic Basis

1.1 Major Types of Immune-Inflammatory Diseases

Immune-mediated inflammatory diseases (IMIDs) are a group of chronic diseases caused by persistent imbalances among innate immunity, adaptive immunity, and the tissue microenvironment. Representative types include inflammatory bowel disease (IBD), rheumatoid arthritis (RA), psoriasis, atopic dermatitis (AD), certain connective tissue diseases, and multiple sclerosis (MS). Pancreatitis, acute lung injury, hepatic inflammation, and peritonitis are not all classified as classical IMIDs. However, their pathological processes also involve innate immune activation, inflammatory cell recruitment, and tissue injury, making them important research targets for induced immune-inflammatory models.

1.2 Common Pathogenic Mechanisms of Immune-Inflammatory Diseases

(1) Barrier damage and innate immune activation

Following damage to tissue barriers such as the intestinal epithelium, skin, and alveolar epithelium, exposure to pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) increases. These signals can be detected by pattern-recognition systems such as TLRs and NLRs. Activation of NF-κB, MAPK, and inflammasome signaling promotes the release of TNF, IL-1β, IL-6, and chemokines and drives myeloid cell recruitment.

(2) Aberrant adaptive immunity

Disruption of self-tolerance or persistent antigenic stimulation can generate abnormal T-cell and B-cell responses. Type II collagen-associated autoimmunity in CIA, myelin antigen-specific T-cell responses in EAE, and Th1-, Th17-, or Th2-biased responses in different colitis models represent distinct forms of adaptive immune dysregulation.

(3) Sustained amplification of inflammatory signaling

Networks such as TNF–NF-κB, IL-6–JAK/STAT3, IL-23/IL-17, and IL-4/IL-13–STAT6 participate in different inflammatory diseases. Once feedback loops are established among immune cells, tissue cells, and inflammatory mediators, transient protective inflammation can develop into a persistent pathological response.

(4) Chronic inflammation and tissue remodeling

Long-term inflammation ultimately manifests as organ-specific structural damage. RA can cause cartilage destruction and bone erosion, MS involves demyelination and neurological injury, chronic IBD is accompanied by recurrent mucosal injury and abnormal repair, and chronic pancreatitis gradually results in acinar cell loss and fibrosis.

Table 1 Pathological Characteristics of Major Immune-Inflammatory Diseases

2 Inflammatory Bowel Disease and Its Induced Models

2.1 Immunopathological Basis of IBD

IBD primarily includes Crohn’s disease and ulcerative colitis. Following disruption of the intestinal epithelial barrier, microorganisms and their components can more readily enter mucosal tissues and activate lamina propria immune cells such as macrophages and dendritic cells. T cells and cytokine networks subsequently maintain inflammation, driving the mucosa into a persistent cycle of injury, inflammation, and abnormal repair. DSS, TNBS, and oxazolone reproduce different aspects of IBD pathology through barrier disruption, hapten sensitization, and distinct T-cell immune biases, respectively.

2.2 DSS-Induced Colitis

(1) Barrier damage and initiation of inflammation

Dextran sulfate sodium (DSS) primarily damages the colonic epithelium and mucosal barrier. Following increased barrier permeability, intestinal microbial components enter the lamina propria, promoting myeloid cell recruitment and inflammatory mediator release. Diarrhea, bloody stool, colon shortening, crypt damage, and inflammatory cell infiltration may subsequently occur.

(2) Model positioning

The DSS model is relatively straightforward to establish and can generate acute, chronic, or relapsing colitis depending on the treatment cycle. It is suitable for investigating the intestinal barrier, innate immunity, mucosal injury, and tissue repair. Disease initiation in this model depends on artificial chemical disruption of the barrier and therefore differs from the natural course of human IBD, which involves the combined effects of genetic susceptibility, the microbiota, and long-term adaptive immune abnormalities.

2.3 TNBS-Induced Colitis

2,4,6-Trinitrobenzenesulfonic acid (TNBS) is a hapten-type chemical sensitizer that can modify tissue proteins and form new immunogenic structures, thereby inducing T cell-mediated intestinal inflammation. The classical model commonly exhibits pronounced Th1/Th17-associated immune characteristics and produces deeper intestinal wall inflammation and tissue injury, making it suitable for studying persistent T cell-associated enteritis. Model severity is readily affected by local administration procedures, animal genetic background, and induction conditions.

2.4 Oxazolone-Induced Colitis

Oxazolone is also a hapten-type sensitizer. Oxazolone-induced colitis generally exhibits prominent Th2/NKT-associated immune characteristics accompanied by enhanced IL-4- and IL-13-related inflammatory programs. This model is suitable for studying Th2-associated mucosal immunity and has a relatively defined immune bias, but it cannot represent the full pathological spectrum of IBD.

Table 2 Comparison of DSS, TNBS, and Oxazolone Models

3 Rheumatoid Arthritis and Its Induced Models

3.1 Immunopathological Basis of RA

(1) Synovial immune inflammation

Persistent synovitis is the central pathological feature of RA. Autoreactive T cells, B cells, macrophages, and fibroblast-like synoviocytes collectively establish an inflammatory microenvironment. Inflammatory mediators such as TNF, IL-1, and IL-6 promote sustained activation and proliferation of synovial tissues.

(2) Destruction of bone and cartilage structures

Persistent inflammation can enhance RANKL-associated osteoclast differentiation and alter cartilage matrix homeostasis, causing synovitis to progress into cartilage destruction and bone erosion. Commonly used induced models include adjuvant-induced arthritis and collagen-induced arthritis, which emphasize strong immune stimulation and autoantigen immunity, respectively.

3.2 Adjuvant-Induced Arthritis

Complete Freund’s adjuvant (CFA) can generate strong and persistent immune stimulation, inducing joint swelling, synovitis, and inflammatory cell infiltration, as well as varying degrees of cartilage and bone damage. Adjuvant-induced arthritis develops relatively rapidly and is suitable for studying inflammatory mediators, immune cell recruitment, and joint tissue injury, although its autoantigen specificity is lower than that of CIA.

3.3 Collagen-Induced Arthritis

(1) Autoantigen immunization

Collagen-induced arthritis (CIA) uses type II collagen (CII) as an antigen and generates immune responses against articular cartilage-associated structures with the assistance of an adjuvant. Both collagen-specific T cells and antibodies participate in disease development.

(2) Model characteristics

CIA can produce synovial hyperplasia, inflammatory cell infiltration, and bone and cartilage destruction. It exhibits more prominent autoimmune characteristics than AIA and is suitable for investigating RA immune mechanisms and structural damage. Animal strain, collagen source, emulsification status, and immunization protocol can all affect disease incidence and severity.

Table 3 Comparison of Adjuvant-Induced Arthritis and CIA Models

4 Multiple Sclerosis and EAE Models

4.1 Immunopathological Basis of MS

The major pathological features of MS include central nervous system inflammation, blood–brain barrier abnormalities, demyelination, and neurological dysfunction. After peripheral myelin antigen-reactive T cells enter the central nervous system, they establish an inflammatory environment together with microglia, macrophages, and other cells. Th1- and Th17-associated immune programs participate in lesion formation. Experimental autoimmune encephalomyelitis (EAE) reproduces certain immune-inflammatory and demyelinating processes of MS through immunization with myelin antigens.

4.2 MOG35–55-Induced EAE

MOG35–55 is an immunogenic fragment of myelin oligodendrocyte glycoprotein that can induce myelin antigen-specific T-cell responses. In C57BL/6 and related genetic backgrounds, it is generally administered with CFA and, depending on the model system, pertussis toxin. Animals may progressively develop reduced tail tone, hindlimb weakness, gait abnormalities, and paralysis, accompanied by central nervous system inflammation and demyelination. This model is commonly used to study persistent or monophasic EAE.

4.3 PLP139–151-Induced EAE

PLP139–151 is derived from myelin proteolipid protein and can induce EAE in mice with specific genetic backgrounds, such as SJL mice, producing a characteristic relapsing–remitting disease course. This system covers immune activation, remission, and subsequent relapse and is suitable for investigating immune mechanisms associated with disease recurrence, although it is strongly dependent on animal genetic background.

Table 4 Comparison of MOG35–55 and PLP139–151 EAE Models

5 Atopic Dermatitis and Cutaneous Inflammation Models

5.1 Immunopathological Basis of AD

(1) Skin barrier abnormalities

Following loss of skin barrier integrity, exogenous antigens, microbial products, and irritants can more readily enter the epidermis and dermis, activating keratinocytes and the local immune system. Barrier abnormalities can both initiate inflammation and maintain chronic cutaneous inflammation.

(2) Amplification of Th2 inflammation

Dendritic cells, mast cells, eosinophils, and T cells collectively participate in local inflammation. Th2-associated cytokines such as IL-4 and IL-13 can further affect the expression of certain barrier proteins, generating a feedback loop between barrier damage and immune inflammation.

5.2 DNFB-Induced Dermatitis Model

1-Fluoro-2,4-dinitrobenzene (DNFB) is a contact-sensitizing hapten that can bind skin proteins and form immunogenic complexes. Following sensitization and repeated challenge, erythema, epidermal thickening, inflammatory cell infiltration, and chronic pruritus may develop. This model is suitable for investigating contact hypersensitivity and AD-like chronic cutaneous inflammation. The system primarily reproduces chemical sensitization-associated skin immune responses and differs from the complex genetic barrier abnormalities of human AD.

5.3 PMA-Induced Cutaneous Inflammation

Phorbol 12-myristate 13-acetate (PMA) activates PKC-related signaling and enhances inflammatory networks such as MAPK and NF-κB, rapidly inducing leukocyte recruitment, tissue edema, and inflammatory mediator release. PMA is suitable for investigating inflammatory initiation and local signal amplification but lacks typical antigen sensitization and the barrier–immune background of AD, making it more appropriate as a general cutaneous inflammation model.

Table 5 Comparison of DNFB and PMA Cutaneous Inflammation Models

6 Induced Models of Acute and Chronic Pancreatitis

6.1 Inflammatory Mechanisms of Pancreatitis

(1) Acute acinar cell injury

Acute pancreatitis (AP) generally begins with abnormal stimulation and injury of pancreatic acinar cells and may be accompanied by disrupted intracellular Ca²⁺ homeostasis, abnormal digestive enzyme activation, mitochondrial damage, and DAMP release. Neutrophils and monocytes/macrophages are subsequently recruited to pancreatic tissues and participate in the amplification of local inflammation.

(2) Chronic tissue remodeling

When acute injury persists or repeatedly occurs, acinar cell loss, pancreatic stellate cell activation, extracellular matrix deposition, and fibrosis can gradually develop, shifting the pathological state toward chronic pancreatitis (CP).

6.2 Caerulein-Induced Acute Pancreatitis

Caerulein is a decapeptide with cholecystokinin-like activity that causes overstimulation of pancreatic acinar cells through CCK receptor-associated signaling. Short-term repeated stimulation can produce pancreatic edema, acinar cell injury, and inflammatory cell infiltration. The model has relatively good reproducibility and is suitable for investigating acute acinar injury and early inflammation. Its lesions are generally highly reversible and differ from some forms of severe necrotizing human AP.

6.3 Chronic Pancreatitis Induced by Repeated Caerulein Administration

Continuous or periodic repeated caerulein stimulation can gradually shift the pancreas from recurrent acute injury to chronic inflammation and tissue remodeling, producing acinar cell loss, stromal activation, and fibrosis. This model is suitable for investigating chronic inflammation and pancreatic fibrosis. The pathological severity is closely associated with the duration and frequency of stimulation and the animal background.

6.4 Other Pancreatitis Induction Systems

Bile salt models primarily reproduce biliary pancreatic injury and can produce pronounced tissue necrosis and inflammation. Basic amino acids such as L-arginine induce pancreatic injury mainly through metabolic stress and acinar cell toxicity. Different systems emphasize acinar overstimulation, biliary injury, or metabolic toxicity and should be selected according to the target pathological process.

Table 6 Comparison of Common Pancreatitis Models

7 Other Common Induced Immune-Inflammatory Models

7.1 Psoriasis-Like Dermatitis and Allergic Airway Inflammation

Imiquimod can establish psoriasis-like cutaneous inflammation through TLR7-associated innate immune activation and the IL-23/IL-17 axis. The model commonly exhibits erythema, scaling, and epidermal hyperplasia. OVA sensitization models are centered on antigen-specific Th2 immunity and can produce eosinophil recruitment, IgE-associated responses, and airway inflammation. They are commonly used to investigate allergic asthma and airway inflammation.

7.2 Hepatic and Pulmonary Inflammation Models

Con A establishes immune-mediated acute liver injury through strong T-cell activation, whereas combined D-galactosamine and LPS treatment produces acute liver injury through hepatocyte sensitization and endotoxin-induced inflammation. Among pulmonary inflammation models, LPS primarily reproduces TLR4-mediated innate immune inflammation, oleic acid mainly causes pulmonary capillary endothelial injury and edema, and bleomycin produces early alveolar epithelial injury and inflammation followed by gradual progression to fibrosis.

7.3 Sterile and Local Inflammation Models

Carrageenan can induce increased local vascular permeability and tissue edema and is commonly used to establish acute inflammatory models such as paw edema. Zymosan can activate pattern-recognition receptors and the complement system and is used to investigate peritonitis and inflammatory cell recruitment. Urate crystals can activate the NLRP3 inflammasome and IL-1β-associated inflammatory programs and are used to reproduce gout-like sterile inflammation.

Table 7 Other Common Induced Inflammation Models

8 Selection Criteria for Induced Immune-Inflammatory Models

8.1 Pathological Initiating Event

The selected model should correspond to the target pathological process. DSS may be prioritized for intestinal epithelial barrier damage, CIA is more appropriate for autoantigen-driven RA research, EAE is required for myelin-specific autoimmunity, and DNFB can be selected for cutaneous contact sensitization. Even when different models all exhibit increased TNF, IL-1β, or IL-6, their upstream pathogenic events may be entirely different.

8.2 Type of Immune Response

Systems such as DSS and LPS exhibit prominent innate immune characteristics, whereas CIA and EAE depend on antigen-specific adaptive immunity. TNBS, oxazolone, and DNFB connect tissue stimulation with T-cell responses through chemical sensitization and are suitable for investigating specific immune biases. Systems involving urate, ATP, or nigericin are more specifically focused on inflammasome activation and sterile inflammation.

8.3 Disease Stage

PMA, LPS, and acute caerulein models primarily reflect rapid inflammation and early tissue injury. Repeated DSS, DNFB, PLP-EAE, and repeated caerulein administration can reproduce persistent inflammation, disease relapse, or tissue remodeling. Acute and chronic models correspond to different pathological stages and cannot be substituted for one another merely by extending the observation period.

8.4 Model Boundaries and Animal Welfare

Induced models generate stable disease phenotypes by intensifying specific pathological processes but cannot fully reproduce the genetic susceptibility, microbiota, environmental exposures, and long-term immune evolution involved in human diseases. Model establishment may also be accompanied by pain, weight loss, impaired mobility, and organ dysfunction. Disease severity scoring, humane endpoints, and necessary analgesic and supportive measures should therefore be established in accordance with animal ethics approval requirements.

9 Products Related to Immune-Inflammatory Disease Models

9.1 Products for Major Disease Modeling Systems

9.2 Products Related to Organ Inflammation, Allergy, and Sterile Inflammation

9.3 Products Related to Innate Immune and Inflammatory Signaling Stimulation

Induced animal models reproduce immune-inflammatory diseases through distinct processes, including barrier injury, autoantigen immunization, chemical sensitization, and organ damage. Each model has a different scope of applicability regarding immune response type, disease stage, and tissue pathology. Future integration of genetic susceptibility backgrounds, the microbiota, humanized systems, and multiomics technologies may further improve the disease relevance and translational value of complex immune-inflammatory models.

References

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[5] Liu T, et al. Vitamin D treatment attenuates 2,4,6-trinitrobenzene sulphonic acid (TNBS)-induced colitis but not oxazolone-induced colitis. Sci Rep. 2016;6:32889.

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[7] Itani S, et al. NLRP3 inflammasome has a protective effect against oxazolone-induced colitis: a possible role in ulcerative colitis. Sci Rep. 2016;6:39075.

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