Intest Res.  2020 Apr;18(2):151-167. 10.5217/ir.2019.09154.

Recent updates on the basic mechanisms and pathogenesis of inflammatory bowel diseases in experimental animal models

• Mizoguchi
• Low D
• Ezaki Y
• Okada T

• KMID: 2501381
• DOI: http://doi.org/10.5217/ir.2019.09154

Abstract

The specific pathogenesis underlining inflammatory bowel disease (IBD) is very complicated, and it is further more difficult to clearly explain the pathophysiology of 2 major forms of IBD, Crohn’s disease (CD) and ulcerative colitis (UC), and both disorders affect individuals throughout life. Despite every extensive effort, the interplay among genetic factors, immunological factors, environmental factors and intestinal microbes is still completely unrevealed. Animal models are indispensable to find out mechanistic details that will facilitate better preclinical setting to target specific components involved in the pathogenesis of IBD. Based on many recent reports, dysbiosis of the commensal microbiota is implicated in the pathogenesis of several diseases, not only IBD but also colon cancer, obesity, psoriasis as well as allergic disorders, in both human and animal models. Advanced technologies including cell-specific and inducible knockout systems, which are recently employed to mouse IBD models, have further enhanced the ability of developing new therapeutic strategies for IBD. Furthermore, data from these mouse models highlight the critical involvement of dysregulated immune responses and impaired colonic epithelial defense system in the pathogenesis of IBD. In this review, we will explain from the history of animal models of IBD to the recent reports of the latest compounds, therapeutic strategies, and approaches tested on IBD animal models.

Keyword

Inflammatory bowel disease; Animal models; Knockout mice; Susceptibility genes; Signal transduction

Figure

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  Fig. 1. Mouse models of IBD with gene targeting strategies. As previously described, mouse models of IBD has been classified into 9 groups based on the gene targeting strategies, which include conventional/cell-specific transgenic (Tg), conventional/ cell-specific knockout (KO), inducible KO (iKO), inducible Tg (iTg), dominant negative (Dn), knock-in (KI), mutagen-induced and innate models. AGR2, anterior gradient protein 2 homolog; Ahr, aryl hydrocarbon receptor; ATF4, activating transcription factor 4; Bach2, BTB domain and CNC homolog 2; Blimp, B-lymphocyte-induced maturation protein; C1galt1, core 1 synthase, glycoprotein-N-acetylgalactosamine 3-beta-galactosyltransferase 1; Casp8, caspase 8; CD4, CD4 positive T cells; Cgamma, common gamma; CPX, carboxypeptidase X; dKO, double KO; Epi, epithelial cells; GARP, glycoprotein-A repetitions predominant protein; GATA3, GATA binding protein 3; Gimap5, GTPase, IMAP family member 5; IEC, intraepithelial lymphocytes; IKK, I kappaB kinase; IL, interleukin; IRE, inositol-requiring enzyme; Itch, itchy E3 ubiquitin protein ligase; Lcn2, lipocalin-2; Mdr1a, multi-drug resistance protein 1a; Mφ, macrophages; Muc2, mucin 2; NEMO, NF-kappa-B essential modulator; NFATc, nuclear factor of activated T cells; Nr2f6; nuclear receptor subfamily 2, group F, member 6; PC, proprotein convertases; PDK1, 3-phosphoinositide-dependent protein kinase 1; Pggt1b, protein geranylgeranyltransferase type 1 subunit beta; PTPN11, tyrosine-protein phosphatase non-receptor type 11; RAG, recombination-activating Conventional KO Cell specific KO Ahr KO (ROR+/-) ATF4 KO14 A2O KO Bach2 KO Cbl-b KO Cgamma KO Gαi2 KO GPX1/2 dDK IL1Rα KO IL2 KO IL2Rα KO IL2Rβ KO IL10 KO Itch KO5 K8 KO Lcn2/IL10 KO7 Mdr1α KO Muc2 KO Nr2f6 KO11 Rhbdf2 KO13 SHIP KO TCRα KO TLR5 KO WASP KO C1galt1/C3Gnt KO9 CD4-PDK1 KO CD4-TSC1 KO CD4-Uhrf1 KO CD4-ADAR1 KO10 CD11-Cnb1 KO12 CX3CR1-IL10Rα KO DC-TGFR II KO DC-β8 KO epi-AP1B KO epi-Casp8 KO epi-C1galt1 KO epi-IKK1/IKK2 dKO epi-IRE1α KO epi-NEMO KO epi-PTPN11 KO epi-RBPJ KO epi-RelA KO epi-TAK1 KO epi-XBP1 KO hema-CD51 KO IEC-Cosmc KO6 MΦ-STAT3 KO Tcell-Blimp-1 KO T cell-Pggt1b KO16 Treg-GARP KO15 Treg-IL10 KO4 Treg-Tbet/GATA3 dKO Thumus-Atg5 KO AGR2 iKO C1galt1 iKO Enteric glia iKO Epi-FASyn iKO SHIP iKO STAT3 iKO TAK1 iKO STAT4 iTg Inducible KO Conventional Tg Dominant negative Cell specific Tg Mutagen induced Knock in Innate B cell-CD154 Tg DC-TNFSF15 Tg Epi-IL15 Tg Liver-CD86 Tg Skin-CD154 Tg T cell-Bcl-3 Tg8 T cell-CD154 Tg T cell-SOCS1 Tg T cell-TNFSF15 Tg IL7 Tg PC KO/PC Tg TCR24 αβ Tg CD4-TGFR II Dn Epi-N cadherin Dn Gimap5 Yipf6 Gp130 Ki P110δ Ki TNF(ARE) Ki IL1rn/RAG dKO NFATc2/RAG dKO Tbet/RAG dKO Figure 1 gene; RBP, retinol-binding protein; Rhbdf2, rhomboid 5 homolog 2; ROR, RAR-related orphan receptor; SHIP, SH-2 containing inositol 5’ polyphosphatase; SOCS1, suppressor of cytokine signaling 1; STAT3, signal transducer and activator of transcription 3; TAK1, transforming growth factor-beta-activated kinase 1; TCR, T cell receptor; TLR, Toll-like receptor; TGFR, transforming growth factor beta receptor; TNFSF, TNF superfamily member 15; Treg, regulatory T cell; WASP, Wiskott-Aldrich syndrome protein; Yipf6, Yip1 domain family member 6; B, B cells; DC, dendritic cells; epi, epithelial cells; Foxp3, regulatory T cells. Modified from Mizoguchi A, et al. J Pathol 2016;238: 205-219 [4].

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  Fig. 2. Major pathogenic factors in T cell receptor alpha chain (TCRα) knockout (KO) mice with colitis. Several factors are involved in the pathogenesis of colitis in TCRα KO mice [3,10]. These mice have unique CD4+ TCRα– β+ T cells, which actively produce IL-4 [43,47].In addition to these characteristic T cells, endogenous as well as exogenous factors are also involved in the pathogenesis of TCRα KO mice. CDR, complementarity determining region; IFN, interferon; IL, interleukin; MHC, major histocompatibility complex; PKC, protein kinase C; TNFR2, TNF receptor 2.

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  Fig. 3. Major pathogenic pathways of IBD in innate versus adaptive immunity. Genetically manipulated murine models of IBD, which are mainly focused on immunological responses have been shown. Mouse models involved in innate immunity and adaptive immunity are shown in light blue and light purple, respectively. ADAR1, adenosine deaminase acting on RNA 1; Ahr, aryl hydrocarbon receptor; Bach2, BTB domain and CNC homolog 2; Blimp1, B-lymphocyte-induced maturation protein 1; DC, dendritic cell; Dn, dominant-negative; GATA3, GATA binding protein 3; Gimap5, GTPase, IMAP family member 5; Itch, itchy E3 ubiquitin protein ligase; Ki, knock-in; KO, knockout; Lrrc32, leucin rich repeat containing 32; NFATc2, nuclear factor of activated T-cells, cytoplasmic 2; PDK1, 3-phosphoinositide-dependent protein kinase 1; PP4, protein phosphatase 4; ROR, RAR-related orphan receptor; Runx3, runt-related transcription factor 3; SHIP, SH-2 containing inositol 5’ polyphosphatase; Tbet, T-box protein 21; TGFRII, transforming growth factor beta receptor type 2; Treg, regulatory T cell; TNFSF15, TNF superfamily member 15; TSC1, tuberous sclerosis complex 1; Uhrf1, ubiquitin-like, containing PHD and RING finger domains 1; WASP, Wiskott-Aldrich syndrome protein.

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  Fig. 4. Major pathogenic pathways of IBD in epithelial defense systems. Genetically manipulated murine models of IBD, which are mainly focused on the deficiency of epithelial defense systems have been shown. AGR2, anterior gradient protein 2 homolog; AP1B, adaptor related protein complex 1 subunit beta 1; Atf4, activating transcription factor 4; C1galt1, core 1 synthase, glycoprotein-N-acetylgalactosamine 3-beta-galactosyltransferase 1; C3 Gnt, core 3 beta 1,3-N-acetylglucosaminyltransferase; Casp8, caspase 8; Epi, epithelial cells; FASyn, fatty acid synthase; GPX, glutathione peroxidase; IRE1, inositol-requiring enzyme 1; Muc2, mucin 2; NEMO, NF-kappa-B essential modulator; NR2F6, nuclear receptor subfamily 2, group F, member 6; TAK1, transforming growth factor-beta activated kinase 1; XBP1, X-box binding protein 1; Yipf6, Yip1 domain family member 6.

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  Fig. 5. Key small molecule compounds. A summary of the key small molecule compounds under development that had undergone evaluation in experimental colitis model and progressed onto successful clinical testing. JAK, Janus kinase; FDA, Food and Drug Administration; S1P, sphingosine-1 phosphate; RIP1, receptor-interacting protein 1; CCR9, chemokine receptor 9.

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