• Bioinformatics
• Inflammatory bowel disease
• Primary sclerosing cholangitis
• Ulcerative colitis

• cytokines
• glomerular cells
• glomerular diseases
• inflammation
• signaling pathway

• Humans
• Kidney Glomerulus/pathology
• Kidney Glomerulus/immunology
• Kidney Glomerulus/metabolism
• Animals
• Inflammation/immunology
• Inflammation/metabolism
• Inflammation/pathology
• Podocytes/immunology
• Podocytes/metabolism
• Glomerulonephritis/immunology
• Glomerulonephritis/pathology
• Glomerulonephritis/metabolism
• Kidney Diseases/immunology
• Kidney Diseases/etiology
• Kidney Diseases/metabolism
• Kidney Diseases/pathology
• Endothelial Cells/immunology
• Endothelial Cells/metabolism
• Inflammation Mediators/metabolism
• Mesangial Cells/immunology
• Mesangial Cells/metabolism
• Cytokines/metabolism

• CRISPR
• gene therapy
• oral disease
• oral microbiome
• periodontal disease
• periodontitis

• PTPN2
• STAT3
• autophagy
• dephosphorylation
• psoriasis

• Animals
• Humans
• Mice
• Cell Line
• Cell Proliferation
• Keratinocytes/metabolism
• Keratinocytes/pathology
• Phosphoric Monoester Hydrolases/metabolism
• Protein Tyrosine Phosphatase, Non-Receptor Type 2/genetics
• Protein Tyrosine Phosphatase, Non-Receptor Type 2/metabolism
• Protein Tyrosine Phosphatase, Non-Receptor Type 2/pharmacology
• Psoriasis/drug therapy
• STAT3 Transcription Factor/metabolism

• PTPN2
• atherosclerosis
• cardiovascular disease
• inflammatory cytokines
• inflammatory response

• Crohns disease
• autophagy
• disease
• gastrointestinal physiology
• homeostasis
• molecular basis of health and disease

• Animals
• Mice
• Genome-Wide Association Study
• Quality of Life
• Inflammatory Bowel Diseases
• Epithelial Cells/metabolism
• Intestinal Mucosa
• Inflammation/metabolism
• Autophagy/genetics

• Paneth Cells
• Signal Transduction
• Homeostasis

• R01 DK117001 NIDDK NIH HHS

• inflammation
• immunological disorders
• target identification

• Autoimmune Diseases/drug therapy
• Autoimmune Diseases/genetics
• Humans
• Inflammation/drug therapy
• Inflammation/genetics
• Inflammation/metabolism
• Phosphoprotein Phosphatases/genetics
• Phosphoprotein Phosphatases/metabolism
• Phosphorylation
• Signal Transduction

• National Natural Science Foundation of China (Nos. 81872877, 81730100, 91853109) National Key R&D Program of China (No. 2017YFA0506000) School of Life Science (NJU)-Sipimo Joint Funds and Mountain-Climbing Talents Project of Nanjing University

• epigenetics
• gut dysbiosis
• immunomodulation
• inflammation
• inflammatory bowel disease

• Colitis, Ulcerative/pathology
• Crohn Disease/pathology
• Dysbiosis
• Gastrointestinal Microbiome/physiology
• Humans
• Inflammatory Bowel Diseases/etiology
• Inflammatory Bowel Diseases/therapy

• Finance Code 001 Coordenação de Aperfeicoamento de Pessoal de Nível Superior
• 306634/2019-8 National Council for Scientific and Technological Development
• E26/202.781/2017 Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro
• E26/210.886/2014 Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro

• Dual allosteric inhibition
• Dynamic analysis
• Molecular dynamics
• Post
• SHP2

Loss-of-function variants of protein tyrosine phosphatase non-receptor type 2 (PTPN2) enhance risk of inflammatory bowel disease and rheumatoid arthritis; however, whether the association between PTPN2 and autoimmune arthritis depends on gut inflammation is unknown. Here we demonstrate that induction of subclinical intestinal inflammation exacerbates development of autoimmune arthritis in SKG mice. Ptpn2-haploinsufficient SKG mice — modeling human carriers of disease-associated variants of PTPN2 — displayed enhanced colitis-induced arthritis and joint accumulation of Tregs expressing RAR-related orphan receptor γT (RORγt) — a gut-enriched Treg subset that can undergo conversion into FoxP3^–IL-17⁺ arthritogenic exTregs. SKG colonic Tregs underwent higher conversion into arthritogenic exTregs when compared with peripheral Tregs, which was exacerbated by haploinsufficiency of Ptpn2. Ptpn2 haploinsufficiency led to selective joint accumulation of RORγt-expressing Tregs expressing the colonic marker G protein–coupled receptor 15 (GPR15) in arthritic mice and selectively enhanced conversion of GPR15⁺ Tregs into exTregs in vitro and in vivo. Inducible Treg-specific haploinsufficiency of Ptpn2 enhanced colitis-induced SKG arthritis and led to specific joint accumulation of GPR15⁺ exTregs. Our data validate the SKG model for studies at the interface between intestinal and joint inflammation and suggest that arthritogenic variants of PTPN2 amplify the link between gut inflammation and arthritis through conversion of colonic Tregs into exTregs.

Loss of protein tyrosine phosphatase non-receptor type 2 amplifies the link between gut and joint inflammation through conversion of colonic Tregs into arthritogenic exTregs.

• Arthritis
• Autoimmune diseases
• Autoimmunity
• Inflammation
• Phosphoprotein phosphatases

Probiotics are known as “live microorganisms” and have been proven to have a health effect on hosts at the proper dose. Recently, a kind of probiotic mixture including eight live bacterial strains, VSL#3, has attracted considerable attention for its combined effect. VSL#3 is the only probiotic considered as a kind of medical food; it mainly participates in the regulation of the intestinal barrier function, including improving tight junction protein function, balancing intestinal microbial composition, regulating immune-related cytokine expression and so on. The objective of this review is to discuss the treatment action and mechanism for the administration of VSL#3 in chronic diseases of animals and humans (including children). We found that VSL#3 has a therapeutic or preventive effect in various systemic diseases per a large number of studies, including digestive systemic diseases (gastrointestinal diseases and hepatic diseases), obesity and diabetes, allergic diseases, nervous systemic diseases, atherosclerosis, bone diseases, and female reproductive systemic diseases.

• VSL#3
• Intestinal barrier function
• Chronic diseases
• Intestinal microbial balance
• Cytokines
• Therapeutic use

• Bowel
• Colitis
• Crohn’s
• Gut
• Inflammatory
• Microbiota

Diabetic nephropathy (DN) is a chronic inflammatory disease triggered by disordered metabolism. Recent studies suggested that protein tyrosine phosphatase non‐receptor type 2 (PTPN2) could ameliorate metabolic disorders and suppress inflammatory responses. This study investigated PTPN2's role in modulating DN and the possible cellular mechanisms involved. In a mouse model combining hyperglycaemia and hypercholesterolaemia (streptozotocin diabetic, ApoE^‐/‐ mice), mice showed severe insulin resistance, renal dysfunction, micro‐inflammation, subsequent extracellular matrix expansion and decreased expression of PTPN2. We found that mice treated with PTPN2 displayed reduced serum creatinine, serum BUN and proteinuria. PTPN2 gene therapy markedly attenuated metabolic disorders and hyperglycaemia. In addition, PTPN2 gene transfer significantly suppressed renal activation of signal transducers and activators of transcription (STAT), STAT‐dependent pro‐inflammatory and pro‐fibrotic genes expression, and influx of lymphocytes in DN, indicating anti‐inflammatory effects of PTPN2 by inhibiting the activation of STAT signalling pathway in vivo. Furthermore, PTPN2 overexpression inhibited the high‐glucose induced phosphorylation of STAT, target genes expression and proliferation in mouse mesangial and tubuloepithelial cells, suggesting that the roles of PTPN2 on STAT activation was independent of glycaemic changes. Our results demonstrated that PTPN2 gene therapy could exert protective effects on DN via ameliorating metabolic disorders and inhibiting renal STAT‐dependent micro‐inflammation, suggesting its potential role for treatment of human DN.

• PTPN2
• STAT1/3
• diabetes nephropathy
• fibrosis
• inflammation

• Northeastern China
• PTPN2
• Polymorphisms
• Psoriasis

Junctional adhesion molecule-A (JAM-A), an epithelial tight junction protein, plays an important role in regulating intestinal permeability through association with a scaffold signaling complex containing ZO-2, Afadin, and the small GTPase Rap2. Under inflammatory conditions, we report that the cytoplasmic tail of JAM-A is tyrosine phosphorylated (p-Y280) in association with loss of barrier function. While barely detectable Y280 phosphorylation was observed in confluent monolayers of human intestinal epithelial cells under basal conditions, exposure to cytokines TNFα, IFNγ, IL-22, or IL-17A, resulted in compromised barrier function in parallel with increased p-Y280. Phosphorylation was Src kinase dependent, and we identified Yes-1 and PTPN13 as a major kinase and phosphatase for p-JAM-A Y280, respectively. Moreover, cytokines IL-22 or IL-17A induced increased activity of Yes-1. Furthermore, the Src kinase inhibitor PP2 rescued cytokine-induced epithelial barrier defects and inhibited phosphorylation of JAM-A Y280 in vitro. Phosphorylation of JAM-A Y280 and increased permeability correlated with reduced JAM-A association with active Rap2. Finally, we observed increased phosphorylation of Y280 in colonic epithelium of individuals with ulcerative colitis and in mice with experimentally induced colitis. These findings support a novel mechanism by which tyrosine phosphorylation of JAM-A Y280 regulates epithelial barrier function during inflammation.

Protein tyrosine phosphatases (PTPs) play a critical role in co-ordinating the signaling networks that maintain lymphocyte homeostasis and direct lymphocyte activation. By dephosphorylating tyrosine residues, PTPs have been shown to modulate enzyme activity and both mediate and disrupt protein-protein interactions. Through these molecular mechanisms, PTPs ultimately impact lymphocyte responses to environmental cues such as inflammatory cytokines and chemokines, as well as antigenic stimulation. Mouse models of acute and chronic intestinal inflammation have been shown to be exacerbated in the absence of PTPs such as PTPN2 and PTPN22. This increase in disease severity is due in part to hyper-activation of lymphocytes in the absence of PTP activity. In accordance, human PTPs have been linked to intestinal inflammation. Genome wide association studies (GWAS) identified several PTPs within risk loci for inflammatory bowel disease (IBD). Therapeutically targeting PTP substrates and their associated signaling pathways, such as those implicated in CD4⁺ T cell responses, has demonstrated clinical efficacy. The current review focuses on the role of PTPs in controlling CD4⁺ T cell activity in the intestinal mucosa and how disruption of PTP activity in CD4⁺ T cells can contribute to intestinal inflammation.

• CD4 T cells
• JAK-STAT
• cytokine
• inflammatory bowel disease
• protein tyrosine phosphatase

• JAK
• STAT
• PTPN2
• Vitamin D3
• diabetes mellitus-associated periodontitis

To investigate whether immune mediated diseases (IMD) are more frequent in patients with inflammatory bowel disease (IBD).

In this population based registry study, a total of 47325 patients with IBD were alive and registered in the Danish National Patient Registry on December 16, 2013. Controls were randomly selected from the Danish Civil Registration System (CRS) and matched for sex, age, and municipality. We used ICD 10 codes to identify the diagnoses of the included patients. The IBD population was divided into three subgroups: Ulcerative colitis (UC), Crohn’s disease (CD) and Both the latter referring to those registered with both diagnoses. Subsequently, odds-ratios (OR) and 95%CI were obtained separately for each group and their respective controls. The use of Bonferoni post-test correction adjusted the significance level to P < 0.00125. P-values were estimated using Fisher’s exact test.

There were significantly more women than men in the registry, and a greater percentage of comorbidity in the IBD groups (P < 0.05). Twenty different IMDs were all significantly more frequent in the IBD group. Sixteen were associated with UC versus twelve with CD. In both UC and CD ORs were significantly increased (P < 0.00125) for primary sclerosing cholangitis (PSC), celiac disease, type 1 diabetes (T1D), sarcoidosis, asthma, iridocyclitis, psoriasis, pyoderma gangrenosum, rheumatoid arthritis, and ankylosing spondylitis. Restricted to UC (P < 0.00125) were autoimmune hepatitis, primary biliary cholangitis, Grave’s disease, polymyalgia rheumatica, temporal arteritis , and atrophic gastritis. Restricted to CD (P < 0.00125) were psoriatic arthritis and episcleritis. Restricted to women with UC (P < 0.00125) were atrophic gastritis, rheumatoid arthritis, temporal arteritis, and polymyalgia rheumatica. Restricted to women with CD were episcleritis, rheumatoid arthritis, and psoriatic arthritis. The only disease restricted to men (P < 0.00125) was sarcoidosis.

Immune mediated diseases were significantly more frequent in patients with IBD. Our results strengthen the hypothesis that some IMDs and IBD may have overlapping pathogenic pathways.

• Immune mediated diseases
• Ulcerative colitis
• Risk
• Prevalence
• Registry
• Chronic inflammatory diseases
• Autoimmune diseases
• Inflammatory bowel disease
• Crohn’s disease
• Extraintestinal manifestations

• Autoimmune Diseases/epidemiology
• Autoimmune Diseases/immunology
• Colitis, Ulcerative/epidemiology
• Colitis, Ulcerative/immunology
• Comorbidity
• Crohn Disease/epidemiology
• Crohn Disease/immunology
• Cross-Sectional Studies
• Denmark/epidemiology
• Female
• Humans
• Inflammation/epidemiology
• Inflammation/immunology
• Male
• Middle Aged
• Odds Ratio
• Registries
• Risk Factors
• Sex Factors

Tumor necrosis factor alpha-induced protein 3 (TNFAIP3) is an anti-inflammatory protein implicated in multiple autoimmune and rheumatologic conditions. We hypothesized that lower levels of TNFAIP3 contributes to excessive cytokine production in response to inflammatory stimuli in axial spondyloarthritis (AxSpA). A further aim was to determine the immune signaling and genetic variation regulating TNFAIP3 expression in individual subjects.

Blood-derived macrophages from 50 AxSpA subjects and 30 healthy controls were assessed for TNFAIP3 expression. Cell lysates were also analyzed for NF-κB, mitogen-activated protein (MAP) kinase and STAT3 phosphorylation, and supernatants for cytokine production. Coding and regulatory regions in the TNFAIP3 gene and other auto-inflammation-implicated genes were sequenced by next-generation sequencing and variants identified.

Mean TNFAIP3 was significantly lower in spondyloarthritis macrophages than controls (p = 0.0085). Spondyloarthritis subject macrophages correspondingly produced more TNF-α in response to lipopolysaccharide (LPS, p = 0.015). Subjects with the highest TNFAIP3 produced significantly less TNF-α in response to LPS (p = 0.0023). Within AxSpA subjects, those on TNF blockers or with shorter duration of disease expressed lower levels of TNFAIP3 (p = 0.0011 and 0.0030, respectively). TNFAIP3 expression correlated positively with phosphorylated IκBα, phosphorylated MAP kinases, and unstimulated phosphorylated STAT3, but negatively with LPS or TNF-α-stimulated fold induction of phosphorylated STAT3. Further, subjects with specific groups of variants within TNFAIP3 displayed differences in TNFAIP3 (p = 0.03–0.004). Nominal pQTL associations with genetic variants outside TNFAIP3 were identified.

Our results suggest that both immune functional and genetic variations contribute to the regulation of TNFAIP3 levels in individual subjects. Decreased expression of TNFAIP3 in AxSpA macrophages correlated with increased LPS-induced TNF-α, and thus, TNFAIP3 dysregulation may be a contributor to excessive inflammatory responses in spondyloarthritis subjects.

• TNF-α
• cytokine production
• genetic variants
• macrophages
• spondyloarthritis
• spondyloarthritis pathogenesis
• tumor necrosis factor alpha-induced protein 3

• Colon cancer
• Inflammation
• Microbiota

T-cell protein tyrosine phosphatase (TC-PTP) has a critical role in the development of the immune system and has been identified as a negative regulator of inflammation. Single-nucleotide polymorphisms in the TC-PTP locus have been associated with increased susceptibility to inflammatory bowel diseases (IBDs) in patients. To further understand how TC-PTP is related to IBDs, we investigated the role of TC-PTP in maintaining the intestinal epithelial barrier using an in vivo genetic approach. Intestinal epithelial cell (IEC)-specific deletion of TC-PTP was achieved in a mouse model at steady state and in the context of dextran sulphate sodium (DSS)-induced colitis. Knockout (KO) of TC-PTP in IECs did not result in an altered intestinal barrier. However, upon DSS treatment, IEC-specific TC-PTP KO mice displayed a more severe colitis phenotype with a corresponding increase in the immune response and inflammatory cytokine profile. The absence of TC-PTP caused an altered turnover of IECs, which is further explained by the role of the tyrosine phosphatase in colonic stem cell (CoSC) proliferation. Our results suggest a novel role for TC-PTP in regulating the homeostasis of CoSC proliferation. This supports the protective function of TC-PTP against IBDs, independently of its previously demonstrated role in intestinal immunity.

• Colonic stem cells
• DSS-induced colitis
• TC-PTP
• intestinal epithelial barrier