MicroRNA-146a reduces MHC-II expression via targeting JAK/STAT signaling in dendritic cells after stem cell transplantation

Abstract

Acute Graft-versus-host disease (GVHD) is a major immunological complication after allogeneic hematopoietic cell transplantation and a better understanding of the molecular regulation of the disease could help to develop novel targeted therapies. Here we found that a G/C polymorphism within the human microRNA-146a (miR-146a) gene of transplant-recipients, which causes reduced miR-146a levels, was strongly associated with the risk of developing severe acute GVHD (n=289). In mice, deficiency of miR-146a in the hematopoietic system or transfer of recipient-type miR 146a-/- dendritic cells (DCs) enhanced GVHD, while miR-146a mimic-transfected-DCs ameliorated disease. Mechanistically, lack of miR-146a enhanced JAK2 STAT1-pathway activity, which led to higher expression of class II-transactivator (CIITA) and consecutively increased MHCII-levels on DCs. Inhibition of JAK1/2 or CIITA knockdown in DCs prevented miR-146a-/- DC-induced GVHD exacerbation. Consistent with our findings in mice, patients with the miR-146a polymorphism rs2910164 in hematopoietic cells displayed higher MHCII levels on monocytes, which could be targeted by JAK1/2-inhibition.Our findings indicate that the miR-146a polymorphism rs2910164 identifies patients at high risk for GVHD before allo HCT. Functionally we show that miR-146a acts as a central regulator of recipient-type DC activation during GVHD by dampening the pro-inflammatory JAK-STAT/CIITA/MHCII axis, which provides a scientific rationale for early JAK1/2-inhibition in selected patients.

Acute Graft-versus-Host Disease — Biologic Process, Prevention, and Therapy

“…Multiple miRs in sera were strongly connected to acute GVHD risk 73 , in particular miR-155 and miR146a 74 . In initial studies, the presence of a miR-146a polymorphism (rs2910164) in the donor or the allo- hematopoietic cell transplant recipient was connected to higher rates of grade III and IV acute GVHD 75,76 , a finding requiring confirmation in larger patient cohorts. These and possibly other yet to be discovered biomarker panels hold promise to better predict the risk of acute GVHD and acute GVHD-related mortality, which could lead to a more individualized GVHD-prophylaxis approach.…”

Advances in understanding the pathogenesis of graft‐versus‐host disease

“…Besides soluble factors in the blood of the GVHD patients, micro‐RNAs, which determine the transcription of multiple target genes were evaluated after allo‐HSCT [reviewed in (Zeiser & Blazar, )]. Functional studies in preclinical models showed that several miRs promoted or inhibited GVHD, such as miR‐155 (Ranganathan et al , ; Chen et al , ), miR100 (Leonhardt et al , ), miR‐146a (Stickel et al , ; Stickel et al , ). The pro‐inflammatory miR‐155 was required for CXCR4‐dependent donor T‐cell migration (Ranganathan et al , ) and NLRP3 inflammasome activation in dendritic cells (Chen et al , ).…”

“…Preclinical studies showed that JAK1/2 inhibition had also a profound effect on DCs and neutrophils in the setting of acute GVHD. JAK1/2 blockade reduced expression of the transcription factor CIITA which activates the MHC class II promoter in DCs (Stickel et al , ) and reduced the migration of recipient neutrophils from the ileum to mesenteric lymph nodes (Hülsdünker et al , ). In May 2019, the JAK1/2 inhibitor ruxolitinib was approved by the US Food and Drug Administration (FDA) for the treatment of acute steroid‐refractory GVHD (FDA, ) based on an open‐label, single‐arm, multicentre study (NCT02953678) of ruxolitinib that enrolled patients with steroid‐refractory acute GVHD grades 2 to 4.…”

Ruxolitinib for the Treatment of Patients with Steroid-Refractory GVHD: An Introduction to the REACH Trials

“…In vitro and in vivo analyses have shown that ruxolitinib affects several aspects of immune function related to GVHD, including inhibiting antigen-presenting cell function through inhibition of DC differentiation, reducing DC migratory capacity [33], decreasing DC expression of major histocompatibility complex class II [34], reducing T-cell proliferation and activation and decreasing cytokine production [35]. Furthermore, ruxolitinib treatment in murine models of GVHD was associated with the amelioration of disease manifestations and symptoms.…”