STAT3 Expression in Host Myeloid Cells Controls Graft-versus-Host Disease Severity

Nieves, Evelyn; Toubai, Tomomi; Peltier, Daniel; Oravecz-Wilson, Katherine; Liu, Chen; Tamaki, Hiroya; Sun, Yaping; Reddy, Pavan

doi:10.1016/j.bbmt.2017.06.018

Cited by 8 publications

(9 citation statements)

References 57 publications

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“…We recently reported an anti-inflammatory function of recipient antigenpresenting cells derived IL-22 from mice with acute GVHD [37]. Interestingly, recipient macrophage-derived Stat3 exerts an anti-GVHD effect [38]. Previous studies mostly focused on the direct immune regulatory role of IL-22.…”

Section: Discussionmentioning

confidence: 99%

IL-22 Accelerates Thymus Regeneration via Stat3/Mcl-1 and Decreases Chronic Graft-versus-Host Disease in Mice after Allotransplants

Pan

Wang

et al. 2019

Biology of Blood and Marrow Transplantation

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High-dose chemotherapy and/or radiation given before an allogeneic hematopoietic cell transplantation severely damage thymic epithelial cells (TECs), resulting in poor post-transplant immune recovery. IL-22 mediates recovery of TECs via a proregenerative effect, but the precise mechanism by which this occurs is unknown. In this study, we found IL-22 improved thymus recovery after damage from irradiation in association with increased number of TECs. This effect was blocked by ruxolitinib, a JAK1/JAK2 inhibitor. IL-22 increased the number of TECs via a Stat3dependent signaling in the mTEC1 murine thymic epithelial cell line. This, in turn, upregulated transcription of myeloid cell leukemia sequence 1 (Mcl1), resulting in increased number of TECs. Similar effects were seen in irradiated mice given IL-22. Defects in IL-22 resulted in delayed thymus recovery in irradiated mice and had an impact on levels of thymus function-related genes such as Foxn1, Aire, and Kgf. In mice, post-transplant use of IL-22 improved repair of TECs, increased the numbers of thymus T cells, increased the intrathymic levels of Aire, and increased the proportion of natural regulatory T cells, resulting in decreased severity of chronic graft-versus-host disease (GVHD). Our data highlight the critical role of the IL-22/Stat3/Mcl-1 pathway in the regeneration of TECs after damage from irradiation in mice and highlight circumstances where normalizing thymus T cell function with IL-22 decreases GVHD after allotransplants.

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Section: Discussionmentioning

confidence: 99%

IL-22 Accelerates Thymus Regeneration via Stat3/Mcl-1 and Decreases Chronic Graft-versus-Host Disease in Mice after Allotransplants

Pan

Wang

et al. 2019

Biology of Blood and Marrow Transplantation

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“…This pathway was previously connected with β2AR signaling (37). Also, it has recently been shown that STAT3 expression in host myeloid cells inhibits GVHD severity through suppressing DC function (38). However, previous studies demonstrated that β2AR agonists activate STAT3 signaling pathway in cardiomyocytes and macrophages and suppress NF-κB (36, 37).…”

Section: Resultsmentioning

confidence: 99%

“…β2AR signaling was previously connected with STAT3 activation (37), which led to increased IL-10 secretion and inhibition of NF-κB (35, 36). Also, it has recently been shown that STAT3 expression in host myeloid cells inhibits GVHD severity through suppressing DC function (38). Through MLR-based in vitro T cell activation and tumor cell killing experiments, we demonstrated that β2AR deficiency in DCs enhances alloreactive CD8 + T cell response in the tumor setting.…”

Section: Discussionmentioning

confidence: 99%

Blockade of Host β2-Adrenergic Receptor Enhances Graft-versus-Tumor Effect through Modulating APCs

Mohammadpour

O’Neil

Qiu

et al. 2018

The Journal of Immunology

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Allogeneic hematopoietic cell transplantation is a potential curative therapy for hematologic malignancies. Host APCs are pivotal to the desired graft-versus-tumor (GVT) effect. Recent studies have shown that β2-adrenergic receptor (β2AR) signaling can have an important impact on immune cell function, including dendritic cells (DCs). In this article, we demonstrate that pretreatment of host mice with a β2AR blocker significantly increases the GVT effect of donor CD8 T cells by decreasing tumor burden without increasing graft-versus-host disease. β2AR-deficient host mice have significantly increased effector memory and central memory CD8 T cells and improved reconstitution of T cells, including CD4Foxp3 regulatory T cells. Notably, β2AR deficiency induces increased CD11c DC development. Also, β2AR-deficient bone marrow-derived DCs induce higher CD8 T cell proliferation and improved tumor killing in vitro. Metabolic profiling shows that β2AR deficiency renders DCs more immunogenic through upregulation of mTOR activity and reduction of STAT3 phosphorylation. Altogether, these findings demonstrate an important role for host β2AR signaling in suppressing T cell reconstitution and GVT activity.

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“…In contrast to the proinflammatory nature of STAT3 signaling in alloreactive T cells, expression of STAT3 in recipient myeloid cells was found to exacerbate GVHD (24). Notably, this analysis was limited to LysM-expressing cells, which are predominantly of the macrophage/monocyte lineage.…”

Section: Stat3 Signaling In Gvhd Of the Gi Tractmentioning

confidence: 99%

“…While this study did not explore a mechanism for why STAT3 signaling in recipient myeloid cells elicits a paradoxical anti-inflammatory effect, the authors did note an increase in the number of donor CD4 + and CD8 + T cells in the spleen and an elevation in serum IFN-γ and IL-17 in LysM-Cre STAT3 fl/− recipients compared to WT recipients, suggesting that this subset of recipient myeloid cells might indirectly regulate donor T cell responses. Interestingly, deficiency in donor myeloid cells had no impact on overall GVHD severity (24). Thus, the proinflammatory effects of STAT3 signaling appear to be mediated through T cells and not myeloid cell populations.…”

Section: Stat3 Signaling In Gvhd Of the Gi Tractmentioning

confidence: 99%

Inflammatory Cytokine Networks in Gastrointestinal Tract Graft vs. Host Disease

Piper

Drobyski

2019

Front. Immunol.

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Graft vs. host disease (GVHD) is the major non-relapse complication associated with allogeneic hematopoietic stem cell transplantation (HSCT). Damage to the gastrointestinal (GI) tract from acute GVHD is a particularly serious event that can result in significant morbidity and mortality. Proinflammatory cytokines play a critical role in the pathophysiology of intestinal GVHD, in part by activating donor T cell populations which subsequently induce tissue damage. In this review, we summarize pre-clinical data derived from experimental murine models that have examined the role of inflammatory cytokine pathways that play critical roles in the pathophysiology of GVHD of the GI tract. Specific areas of focus are on STAT 3-dependent cytokines (e.g., IL-6, IL-23, and IL-21), and members of the IL-1 cytokine family, both of which have been shown to induce pathological damage within the GI tract during this disease. We also review established and ongoing efforts to translate these pre-clinical findings into the clinic in an effort to reduce morbidity and mortality due to this complication.

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STAT3 Expression in Host Myeloid Cells Controls Graft-versus-Host Disease Severity

Cited by 8 publications

References 57 publications

IL-22 Accelerates Thymus Regeneration via Stat3/Mcl-1 and Decreases Chronic Graft-versus-Host Disease in Mice after Allotransplants

IL-22 Accelerates Thymus Regeneration via Stat3/Mcl-1 and Decreases Chronic Graft-versus-Host Disease in Mice after Allotransplants

Blockade of Host β2-Adrenergic Receptor Enhances Graft-versus-Tumor Effect through Modulating APCs

Inflammatory Cytokine Networks in Gastrointestinal Tract Graft vs. Host Disease

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