Stable form of galectin-9, a Tim-3 ligand, inhibits contact hypersensitivity and psoriatic reactions: A potent therapeutic tool for Th1- and/or Th17-mediated skin inflammation

Niwa, Haruna; Satoh, Takahiro; Matsushima, Yuki; Hosoya, K.; Saeki, Kazumi; Niki, Toshiro; Hirashima, Mitsuomi; Yokozeki, Hiroo

doi:10.1016/j.clim.2009.04.012

Cited by 75 publications

(53 citation statements)

References 37 publications

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“…Late cornified envelope (Lce) is a stratum-corneum protein involved in barrier formation (32). Galectin-9 (Lgals9) reduces Th1-mediated skin inflammation and thus inhibits contact hypersensitivity and psoriatic reactions in experimental animal models (33). The absence of Blimp-1 in keratinocytes, leading to altered expression of the foregoing genes, may account for the abnormal growth and cornification of keratinocytes, as well as skin inflammation.…”

Section: Discussionmentioning

confidence: 99%

Inducible deletion of the Blimp-1 gene in adult epidermis causes granulocyte-dominated chronic skin inflammation in mice

Chiang

Yang

Lin

et al. 2013

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

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B lymphocyte-induced maturation protein-1 (Blimp-1) is a transcriptional repressor important for the differentiation and function of several types of immune cells. Because skin serves as a physical barrier and acts as an immune sentinel, we investigated whether Blimp-1 is involved in epidermal immune function. We show that Blimp-1 expression is reduced in skin lesions of some human eczema samples and in stimulated primary keratinocytes. Epidermal-specific deletion of PR domain containing 1, with ZNF domain ( Prdm1 ), the gene encoding Blimp-1, in adult mice caused spontaneously inflamed skin characterized by massive dermal infiltration of neutrophils/macrophages and development of chronic inflammation associated with higher levels of cytokines/chemokines, including granulocyte colony-stimulating factor (G-CSF), and enhanced myelopoiesis in bone marrow. Deletion of Prdm1 in the epidermis of adult mice also led to stronger inflammatory reactions in a tape-stripping test and in a disease model of contact dermatitis. The elevated G-CSF produced by keratinocytes after deletion of Prdm1 in vitro was mediated by the transcriptional activation of FBJ osteosarcoma oncogene ( Fos ) and fos-like antigen 1 ( Fosl1 ). Systemic increases in G-CSF contributed to the inflammatory responses, because deletion of the G-CSF gene [colony stimulating factor 3, ( Csf3 )] prevented neutrophilia and partially ameliorated the inflamed skin in Prdm1- deficient mice. Our findings indicate a previously unreported function for Blimp-1 in restraining steady-state epidermal barrier immunity.

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Section: Discussionmentioning

confidence: 99%

Inducible deletion of the Blimp-1 gene in adult epidermis causes granulocyte-dominated chronic skin inflammation in mice

Chiang

Yang

Lin

et al. 2013

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

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“…Galectin-1, either exogenously supplied or regulated endogenously, drove the differentiation of DCs toward a regulatory function, promoting T cell tolerance [34] [15]. Most evidence pointing to gal-1 as a negative regulator of the immune response has been gathered in animal models of inflammatory diseases, and studies in human disease are comparatively scarce.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, a recent study described a beneficial effect of gal-9 treatment in a model of IL-23-induced, psoriasis-like skin inflammation [15]. To examine the potential role of galectins in the immunopathogenesis of psoriasis, we analyzed the expression of gal-1, gal-3 and gal-9 in psoriasis patients, and related this to the levels of Th1/Th17 cytokines.…”

Section: Introductionmentioning

confidence: 99%

Psoriasis in humans is associated with down‐regulation of galectins in dendritic cells

Fuente

Pérez‐Gala

Bonay

et al. 2012

The Journal of Pathology

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2 ABSTRACT.We have investigated the expression and role of galectin-1 and other galectins in psoriasis and in the Th1/Th17 effector and dendritic cell responses associated with this chronic inflammatory skin condition. To determine differences between psoriasis patients and healthy donors, galectins expression was analyzed by RT-PCR assays in skin samples and specifically on epidermal and peripheral blood dendritic cells by immunofluorescence and flow cytometry.In skin of healthy donors galectins 1, 3 and 9 were expressed in a high proportion of Langerhans cells. Also, galectins were differentially expressed in peripheral blood dendritic cell subsets; galectin-1 and galectin-9 were highly expressed in peripheral myeloid dendritic cells compared with plasmacytoid dendritic cells. We found that non-lesional as well as lesional skin samples from psoriasis patients had low levels of galectin-1 at mRNA and protein level in parallel with low levels of IL-10 mRNA compared with skin from healthy patients. However, only lesional skin samples expressed high levels of

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“…Indeed, binding of Tim-3 to its natural ligand galectin-9 (Gal-9) induces T cell death and tolerance in vivo (15,16). However, subsequent data showed that Tim-3 is also constitutively expressed on macrophages and dendritic cells and regulates the innate immune response (17)(18)(19).…”

mentioning

confidence: 99%

T Cell Ig Mucin-3 Promotes Homeostasis of Sepsis by Negatively Regulating the TLR Response

Yang

Jiang

Chen

et al. 2013

The Journal of Immunology

121

139

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Sepsis is an excessive inflammatory condition with a high mortality rate and limited prediction and therapeutic options. In this study, for the first time, to our knowledge, we found that downregulation and/or blockade of T cell Ig and mucin domain protein 3 (Tim-3), a negative immune regulator, correlated with severity of sepsis, suggesting that Tim-3 plays important roles in maintaining the homeostasis of sepsis in both humans and a mouse model. Blockade and/or downregulation of Tim-3 led to increased macrophage activation, which contributed to the systemic inflammatory response in sepsis, whereas Tim-3 overexpression in macrophages significantly suppressed TLR-mediated proinflammatory cytokine production, indicating that Tim-3 is a negative regulator of TLR-mediated immune responses. Cross-talk between the Tim-3 and TLR4 pathways makes TLR4 an important contributor to Tim-3–mediated negative regulation of the innate immune response. Tim-3 signaling inhibited LPS–TLR4–mediated NF-κB activation by increasing PI3K–AKT phosphorylation and A20 activity. This negative regulatory role of Tim-3 reflects a new adaptive compensatory and protective mechanism in sepsis victims, a finding of potential importance for modulating innate responses in these patients.

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Stable form of galectin-9, a Tim-3 ligand, inhibits contact hypersensitivity and psoriatic reactions: A potent therapeutic tool for Th1- and/or Th17-mediated skin inflammation

Cited by 75 publications

References 37 publications

Inducible deletion of the Blimp-1 gene in adult epidermis causes granulocyte-dominated chronic skin inflammation in mice

Inducible deletion of the Blimp-1 gene in adult epidermis causes granulocyte-dominated chronic skin inflammation in mice

Psoriasis in humans is associated with down‐regulation of galectins in dendritic cells

T Cell Ig Mucin-3 Promotes Homeostasis of Sepsis by Negatively Regulating the TLR Response

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