Sequential activation of inflammatory signaling pathways during graft-versus-host disease (GVHD): Early role for STAT1 and STAT3

143

147

Key Points• IL-33 and ST2 expression are increased post-conditioning and with GVHD, resulting in increased T-cell activation via the IL-33/ST2 axis.• Infusion of ST2-Fc protein exploits sST2's function as a negative regulator of acute GVHD inhibiting proinflammatory cytokines.Interleukin (IL)-33 binding to the receptor suppression of tumorigenicity 2 (ST2) produces pro-inflammatory and anti-inflammatory effects. Increased levels of soluble ST2 (sST2) are a biomarker for steroid-refractory graft-versus-host disease (GVHD) and mortality. However, whether sST2 has a role as an immune modulator or only as a biomarker during GVHD was unclear. We show increased IL-33 production by nonhematopoietic cells in the gastrointestinal (GI) tract in mice post-conditioning and patients during GVHD. Exogenous IL-33 administration during the peak inflammatory response worsened GVHD. Conversely, GVHD lethality and tumor necrosis factor-a production was significantly reduced in il33 2/2 recipients. ST2 was upregulated on murine and human alloreactive T cells and sST2 increased as experimental GVHD progressed. Concordantly, st2 2/2 vs wild-type (WT) donor T cells had a marked reduction in GVHD lethality and GI histopathology. Alloantigen-induced IL-18 receptor upregulation was lower in st2 2/2 T cells, and linked to reduced interferon-g production by st2 2/2 vs WT T cells during GVHD. Blockade of IL-33/ST2 interactions during allogeneic-hematopoietic cell transplantation by exogenous ST2-Fc infusions had a marked reduction in GVHD lethality, indicating a role of ST2 as a decoy receptor modulating GVHD. Together, these studies point to the IL-33/ST2 axis as a novel and potent target for GVHD therapy. (Blood. 2015;125(20):3183-3192)

Section: Discussionmentioning

confidence: 99%

The IL-33/ST2 axis augments effector T-cell responses during acute GVHD

Reichenbach

Schwarze

Matta

et al. 2015

143

147

“…We therefore focused on other pathways that promote inflammation in GVHD, such as MAPK signaling. 31 34 The connection between miR-155 and P2Y12 and P2Y2, however, might be operational during the priming phase of GVHD in vivo. In addition, we consistently observed reduced inflammasome-related gene expression in miR-155 2/2 DCs compared with WT DCs.…”

Section: Discussionmentioning

confidence: 99%

“…To better understand the defect in miR-155 2/2 DCs, we analyzed gene sets that have been shown to be relevant in GVHD, including the mitogen-activated protein kinase (MAPK) signaling pathway 31 and the inflammasome complex. 4 The microarray analysis revealed dysregulated expression of MAPK family genes in miR-155 2/2 DCs compared with WT DCs ( Figure 4A).…”

Section: Mir-155 2/2 Dcs Display a Reduced Mitogen-activated Protein mentioning

confidence: 99%

MicroRNA-155–deficient dendritic cells cause less severe GVHD through reduced migration and defective inflammasome activation

Chen

Smith

Iype

et al. 2015

100

Key Points• GVHD induction is dependent on functional miR-155 in DCs of the allo-HCT recipient.• MiR-155 deficiency reduces ATP-mediated cell migration, ERK and inflammasome activation, and IL-1b production of DCs.The successful treatment of acute leukemias with allogeneic hematopoietic cell transplantation (allo-HCT) is limited by acute graft-versus-host disease (GVHD). Because microRNA-155 (miR-155) regulates activation of the innate immune system, we aimed to determine its function in dendritic cells (DCs) during GVHD in an experimental model. We observed that miR-155 deficiency of the recipient led to improved survival, reduced serum levels of proinflammatory cytokines, and lower GVHD histopathology scores. In addition, miR-155 2/2 bone marrow chimeric mice receiving allo-HCT and miR-155 2/2 DCs showed that miR-155 deficiency in the DC compartment was responsible for protection from GVHD. Activated miR-155 2/2 DCs displayed lower expression of various purinergic receptors and impaired migration toward adenosine triphosphate (ATP). Microarray analysis of lipopolysaccharide/ATP-stimulated miR-155 2/2 DCs revealed mitogen-activated protein kinase pathway dysregulation and reduced inflammasome-associated gene expression. Consistent with this gene expression data, we observed reduced ERK activation, caspase-1 cleavage, and IL-1b production in miR-155 2/2 DCs. The connection between miR-155 and inflammasome activation was supported by the fact that Nlrp3/miR-155 double-knockout allo-HCT recipient mice had no increased protection from GVHD compared with Nlrp3 2/2 recipients. This study indicates that during GVHD, miR-155 promotes DC migration toward sites of ATP release accompanied by inflammasome activation. Inhibiting proinflammatory miR-155 by antagomir treatment could help reduce this complication of allo-HCT. (Blood. 2015;126(1):103-112)

“…In a murine model of aGVHD, STAT1 and STAT3 in CD4 1 and CD8 1 T cells were shown to be activated in an early stage of disease. 12 If STAT1 was missing in donor splenocytes, clinical GVHD signs and the disease-related mortality were significantly impaired, both in the minor and major mismatch setting. 13 Here we show that JAK1/2 inhibition by ruxolitinib potently reduced aGVHD in mice and significantly prolonged survival, even in an aggressive major mismatch model.…”

Section: Introductionmentioning

confidence: 99%

Activity of therapeutic JAK 1/2 blockade in graft-versus-host disease

Spoerl

Mathew²,

Bscheider

et al. 2014

356

296

Key Points• We report that ruxolitinib reduces murine GVHD via increased Treg numbers.• We demonstrate the potent activity of ruxolitinib treatment in patients with corticosteroidrefractory GVHD.Graft-versus-host-disease (GVHD) is a severe complication of allogeneic hematopoietic cell transplantation (allo-HCT) characterized by the production of high levels of proinflammatory cytokines. Activated Janus kinases (JAKs) are required for T-effector cell responses in different inflammatory diseases, and their blockade could potently reduce acute GVHD. We observed that inhibition of JAK1/2 signaling resulted in reduced proliferation of effector T cells and suppression of proinflammatory cytokine production in response to alloantigen in mice. In vivo JAK 1/2 inhibition improved survival of mice developing acute GVHD and reduced histopathological GVHD grading, serum levels of proinflammatory cytokines, and expansion of alloreactive luc-transgenic T cells. Mechanistically, we could show that ruxolitinib impaired differentiation of CD4 1 T cells into IFN-g-and IL17A-producing cells, and that both T-cell phenotypes are linked to GVHD. Conversely, ruxolitinib treatment in allo-HCT recipients increased FoxP3 1 regulatory T cells, which are linked to immunologic tolerance. Based on these results, we treated 6 patients with steroid-refractory GVHD with ruxolitinib. All patients responded with respect to clinical GVHD symptoms and serum levels of proinflammatory cytokines. In summary, ruxolitinib represents a novel targeted approach in GVHD by suppression of proinflammatory signaling that mediates tissue damage and by promotion of tolerogenic Treg cells. (Blood. 2014;123(24):3832-3842)