Constitutive Type I Interferon Modulates Homeostatic Balance through Tonic Signaling

Gough, Daniel J.; Messina, Nicole L.; Clarke, Christopher J.; Johnstone, Ricky W.; Levy, David E.

doi:10.1016/j.immuni.2012.01.011

Cited by 392 publications

(430 citation statements)

References 98 publications

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“…In line with these findings, we also found in the gingiva of Gas6 −/− mice higher levels of IL-17A and IFN-α mRNA, the latter known, even at low expression levels, to shape tonic signals by modulating cytokine expression and therefore regulating tissue homeostasis ( Fig. 3 E and F) (16). Collectively, these results indicate that the lack of GAS6 resulted in an increased inflammatory milieu in the oral mucosa.…”

Section: Resultssupporting

confidence: 86%

GAS6 is a key homeostatic immunological regulator of host–commensal interactions in the oral mucosa

Nassar

Tabib

Capucha

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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The oral epithelium contributes to innate immunity and oral mucosal homeostasis, which is critical for preventing local inflammation and the associated adverse systemic conditions. Nevertheless, the mechanisms by which the oral epithelium maintains homeostasis are poorly understood. Here, we studied the role of growth arrest specific 6 (GAS6), a ligand of the TYRO3–AXL–MERTK (TAM) receptor family, in regulating oral mucosal homeostasis. Expression of GAS6 was restricted to the outer layers of the oral epithelium. In contrast to protein S, the other TAM ligand, which was constitutively expressed postnatally, expression of GAS6 initiated only 3–4 wk after birth. Further analysis revealed that GAS6 expression was induced by the oral microbiota in a myeloid differentiation primary response gene 88 (MyD88)-dependent fashion. Mice lacking GAS6 presented higher levels of inflammatory cytokines, elevated frequencies of neutrophils, and up-regulated activity of enzymes, generating reactive nitrogen species. We also found an imbalance in Th17/Treg ratio known to control tissue homeostasis, as Gas6-deficient dendritic cells preferentially secreted IL-6 and induced Th17 cells. As a result of this immunological shift, a significant microbial dysbiosis was observed in Gas6−/− mice, because anaerobic bacteria largely expanded by using inflammatory byproducts for anaerobic respiration. Using chimeric mice, we found a critical role for GAS6 in epithelial cells in maintaining oral homeostasis, whereas its absence in hematopoietic cells synergized the level of dysbiosis. We thus propose GAS6 as a key immunological regulator of host–commensal interactions in the oral epithelium.

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Section: Resultssupporting

confidence: 86%

GAS6 is a key homeostatic immunological regulator of host–commensal interactions in the oral mucosa

Nassar

Tabib

Capucha

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…In light of multiple reports showing tumor immunity in these models (25,26), and the fact that tonic IFN signaling is required to maintain normal hematopoiesis (27), our data indicate a role for the immune system in regulating metastatic spread. In support of this, the loss of hematopoietic Ifnar1 [by using chimeras made from WT recipients and normal (WT) or IFN-insensitive (Ifnar1 À/À ) bone marrow] reduced metastasis-free survival in the 4T1.2 model-an aggressive variant of the 4T1 line-in the absence of an impact on orthotopic tumor growth (Supplementary Fig.…”

Section: Resultssupporting

confidence: 58%

Loss of Host Type-I IFN Signaling Accelerates Metastasis and Impairs NK-cell Antitumor Function in Multiple Models of Breast Cancer

Rautela

Baschuk

Slaney

et al. 2015

Cancer Immunology Research

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Metastatic progression is the major cause of breast cancerrelated mortality. By examining multiple syngeneic preclinical breast cancer models in mice lacking a functional type-I interferon receptor (Ifnar1 À/À mice), we show that host-derived type-I interferon (IFN) signaling is a critical determinant of metastatic spread that is independent of primary tumor growth. In particular, we show that bone metastasis can be accelerated in Balb/c Ifnar1 À/À mice bearing either 4T1 or 66cl4 orthotopic tumors and, for the first time, present data showing the development of bone metastasis in the C57Bl/6 spontaneous MMTV-PyMT-driven model of tumorigenesis. Further exploration of these results revealed that endogenous type-I IFN signaling to the host hematopoietic system is a key determinant of metastasis-free survival and critical to the responsiveness of the circulating natural killer (NK)-cell population. We find that in vivo-stimulated NK cells derived from wild-type, but not Ifnar1 À/À , mice can eliminate the 4T1 and 66cl4 breast tumor lines with varying kinetics in vitro. Together, this study indicates that the dysregulated immunity resulting from a loss of host type-I IFN signaling is sufficient to drive metastasis, and provides a rationale for targeting the endogenous type-I IFN pathway as an antimetastatic strategy.

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“…Tyk2 is an essential element of the tonic signal induced by homeostatic IFN-b and is implicated in signaling networks initiated by a large number of immunoregulatory cytokines (9,52). As first proposed by Shaw et al (6) and later supported by human disease genetic-association studies, notably MS, naturally occurring mutations in the Tyk2 gene may underlie altered susceptibility to autoimmune disorders (Table I).…”

mentioning

confidence: 98%

Two Rare Disease-Associated Tyk2 Variants Are Catalytically Impaired but Signaling Competent

Gakovic

Ragimbeau

et al. 2013

The Journal of Immunology

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Tyk2 belongs to the Janus protein tyrosine kinase family and is involved in signaling of immunoregulatory cytokines (type I and III IFNs, IL-6, IL-10, and IL-12 families) via its interaction with shared receptor subunits. Depending on the receptor complex, Tyk2 is coactivated with either Jak1 or Jak2, but a detailed molecular characterization of the interplay between the two enzymes is missing. In human populations, the Tyk2 gene presents high levels of genetic diversity with >100 nonsynonymous variants being detected. In this study, we characterized two rare Tyk2 variants, I684S and P1104A, which have been associated with susceptibility to autoimmune disease. Specifically, we measured their in vitro catalytic activity and their ability to mediate Stat activation in fibroblasts and genotyped B cell lines. Both variants were found to be catalytically impaired but rescued signaling in response to IFN-α/β, IL-6, and IL-10. These data, coupled with functional study of an engineered Jak1 P1084A, support a model of nonhierarchical activation of Janus kinases in which one catalytically competent Jak is sufficient for signaling provided that its partner behaves as proper scaffold, even if inactive. Through the analysis of IFN-α and IFN-γ signaling in cells with different Jak1 P1084A levels, we also illustrate a context in which a hypomorphic Jak can hamper signaling in a cytokine-specific manner. Given the multitude of Tyk2-activating cytokines, the cell context–dependent requirement for Tyk2 and the catalytic defect of the two disease-associated variants studied in this paper, we predict that these alleles are functionally significant in complex immune disorders.

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Constitutive Type I Interferon Modulates Homeostatic Balance through Tonic Signaling

Cited by 392 publications

References 98 publications

GAS6 is a key homeostatic immunological regulator of host–commensal interactions in the oral mucosa

GAS6 is a key homeostatic immunological regulator of host–commensal interactions in the oral mucosa

Loss of Host Type-I IFN Signaling Accelerates Metastasis and Impairs NK-cell Antitumor Function in Multiple Models of Breast Cancer

Two Rare Disease-Associated Tyk2 Variants Are Catalytically Impaired but Signaling Competent

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