Loss of Protein Tyrosine Phosphatase Nonreceptor Type 22 Regulates Interferon-γ–Induced Signaling in Human Monocytes

Spalinger, Marianne R.; Lang, Silvia; Weber, Achim; Frei, Pascal; Fried, Michael; Rogler, Gerhard; Scharl, Michael

doi:10.1053/j.gastro.2013.01.048

Cited by 49 publications

(76 citation statements)

References 38 publications

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“…The expression pattern of PTPN22, uninduced during M1 but induced during M2 polarization, further allows M1 polarization to proceed and facilitates the expression of M2-associated genes. Our findings are consistent with a recent report showing that knocking down PTPN22 in human THP-1 monocytic cells resulted in heightened IFN-g-induced expression of IL-6 (28).…”

Section: Discussionsupporting

confidence: 94%

PTPN22 Modulates Macrophage Polarization and Susceptibility to Dextran Sulfate Sodium–Induced Colitis

Chang

Miaw

Tseng

et al. 2013

The Journal of Immunology

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PTPN22, a protein tyrosine phosphatase expressed mainly in hematopoietic cells, has been linked to many autoimmune diseases. A C-to-T single nucleotide polymorphism (SNP) at position 1858 of human PTPN22 cDNA decreases the risk of Crohn’s disease. However, the function of PTPN22 and the mechanism by which this SNP reduces the risk of Crohn’s disease are poorly understood. We find that PTPN22 is expressed in macrophages. It suppresses M1 macrophage polarization and reciprocally promotes the expression of M2-associated genes. PTPN22-deficient mice develop severe colitis induced by dextran sulfate sodium, and their intestinal macrophages express higher levels of M1 genes but lower levels of M2-associated genes. Furthermore, the protective T allele of the C1858T SNP is associated with attenuated expression of inflammatory cytokines and a higher level of PTPN22 in human M1 macrophages. This T allele–associated aberrant expression of PTPN22 is partly attributed to an autoinhibition mechanism, in which PTPN22 suppresses its own expression in M1 but not M2 macrophages. Our data not only demonstrate a critical role of PTPN22 in regulating macrophage polarization but also provide a molecular explanation for the protective effect of the C1858T SNP in Crohn’s disease.

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Section: Discussionsupporting

confidence: 94%

PTPN22 Modulates Macrophage Polarization and Susceptibility to Dextran Sulfate Sodium–Induced Colitis

Chang

Miaw

Tseng

et al. 2013

The Journal of Immunology

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“…PTPN22 also controls bacterial-induced signaling cascades [29] and a variant within the PTPN22 gene locus protects from CD [30]. In CD, intestinal levels of PTPN22 are reduced, resulting in enhanced secretion of IL-6 but reduced IL-12 secretion [31]. This leads to a skewed response to pathogens inducing a cytokine profile favoring pathogenic Th17 cell proliferation.…”

Section: Immune Cells and Pattern Recognition Receptorsmentioning

confidence: 99%

Crohn's Disease: Loss of Tolerance or a Disorder of Autophagy?

Spalinger

Rogler

Scharl

2014

Dig Dis

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Crohn's disease (CD) is characterized by a breakdown of the intestinal epithelial barrier function leading to an uncontrolled immune response to bacterial antigens. Available data demonstrate that appropriate response and early host defense against invading bacteria are crucial to maintain tolerance towards commensal bacteria. When the mechanisms of early removal of invading bacteria are disturbed, a loss of tolerance and a full-blown adaptive immune reaction, which is mounted against the usually harmless commensal flora, are induced. Dysfunction of autophagy caused by genetic variations within CD susceptibility genes, such as ATG16L1 and IRGM, results in defective handling of intracellular and invading bacteria and causes prolonged survival and defective clearance of those microbes. Dysfunction of ATG16L1 and IRGM has also been shown to cause aberrant Paneth cell function and uncontrolled secretion of proinflammatory cytokines finally resulting in increased susceptibility to bacterial infection and the onset of colitis. Interestingly, autophagy can also be regulated by other CD susceptibility genes, such as NOD2 (nucleotide oligomerization domain 2) or PTPN2 (protein tyrosine phosphatase nonreceptor type 2) and the presence of the CD-associated variations within these genes results in similar effects. Taken together, more and more evidence suggests a close functional correlation between loss of tolerance and defective autophagy in CD patients. Therefore, most likely, the onset of CD is triggered by both a loss of tolerance as well as a dysfunction of autophagy, which finally results in the onset of chronic intestinal inflammation.

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“…We considered that the pro-inflammatory cytokines in SLE patients with severe disease activity could contribute to the low expression of PTPN22 mRNA, given that an in vitro study in THP-1 human cells that was stimulated with TNF-a and IL-1b show a low PTPN22 mRNA and protein levels, whereas stimulation with IL-6 and IL-23 increases their expression. Furthermore, it has been observed that under different conditions of IFN-c, the THP-1 cells increase or decrease the PTPN22 mRNA expression [49]. In the future, it would be interesting to analyze the relationship between cytokine profiles with PTPN22 mRNA expression and Lyp protein, in order to elucidate whether their expression is altered.…”

Section: Discussionmentioning

confidence: 99%

Distribution of PTPN22 polymorphisms in SLE from western Mexico: correlation with mRNA expression and disease activity

et al. 2015

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Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune inflammatory disease characterized by loss of self-tolerance with hyperactivation of autoreactive T and B cells. Protein tyrosine phosphatase non-receptor type 22 (PTPN22) encodes for lymphoid-specific phosphatase (Lyp), which is a key negative regulator of T lymphocyte activation. The aim of this study was to evaluate the genetic contribution of PTPN22 -1123G>C and +1858C>T polymorphisms and their haplotypes in SLE patients, as well as mRNA expression according to -1123G>C promoter polymorphism and disease activity. One hundred and fifty SLE patients and 150 unrelated healthy controls (HC), both Mexican mestizos, were genotyped by PCR-RFLP technique for the PTPN22 -1123G>C and +1858C>T polymorphisms. PTPN22 mRNA expression levels were determined by real-time PCR from PBMCs of thirty patients with SLE and fifteen HC carrying different genotypes. Distributions of genotype and allelic frequencies were similar between SLE and HC. The most frequent alleles were -1123 G and +1858 C in both groups (69 vs. 66 % and 97 vs. 98 %, in SLE and HC, respectively). However, the recessive model of inheritance analysis showed a lower frequency of -1123 CC genotype in SLE patients (7 vs. 15 %), suggesting a protection effect to develop SLE (OR 0.41, CI 1.10-5.28, p = 0.02). Haplotype analysis showed strong linkage disequilibrium D' = 0.98 for PTPN22 -1123G>C and +1858C>T polymorphisms, but haplotypes were not associated with SLE. The PTPN22 mRNA expression did not show differences among -1123G>C genotypes; nevertheless, a significant negative correlation with disease activity was found (r = -0.64, p < 0.01). SLE inactive patients showed similar PTPN22 mRNA expression levels to healthy controls, whereas in patients with severe flare, the expression was nearly depleted. In conclusion, we found a lack of association of PTPN22 -1123G>C and +1858C>T polymorphisms with the risk of developing SLE in a Mexican population. Moreover, decreased or absent PTPN22 mRNA expression in SLE patients with severe flare suggests that Lyp plays an important regulatory role, and its absence contributes to the inflammatory response and disease activity in SLE. However, further analysis in a prospective study could help us determine its usefulness as a genetic marker of disease activity in SLE.

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Loss of Protein Tyrosine Phosphatase Nonreceptor Type 22 Regulates Interferon-γ–Induced Signaling in Human Monocytes

Cited by 49 publications

References 38 publications

PTPN22 Modulates Macrophage Polarization and Susceptibility to Dextran Sulfate Sodium–Induced Colitis

PTPN22 Modulates Macrophage Polarization and Susceptibility to Dextran Sulfate Sodium–Induced Colitis

Crohn's Disease: Loss of Tolerance or a Disorder of Autophagy?

Distribution of PTPN22 polymorphisms in SLE from western Mexico: correlation with mRNA expression and disease activity

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