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iNature
Non-hematopoietic cells, including epithelial and stromal cells, are also important for enhancing or suppressing the inflammatory immune response, especially at "barrier sites"
such as the gastrointestinal tract and skin.
The gastrointestinal tract is key to inducing many T cell-mediated inflammatory diseases, including graft-versus-host disease (GVHD)
in individuals undergoing allogeneic hematopoietic cell transplantation (allogeneic-HCT).
Heterologous T cell-mediated gastrointestinal injury is a determinant of GVHD severity
.
Intestinal epithelial cells (IECs) are associated with the proliferation of T cell-mediated inflammatory diseases, including GVHD, but the underlying mechanism is unknown
.
On November 10, 2022, Suzhou Sultan He Research Group, Suzhou Institute of Systematic Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, published an online report entitled "A Novel RIPK1 Inhibitor Reduces GVHD in Mice via a Non-immunosuppressive Mechanism that Restores" in Blood (IF=25) magazine Intestinal Homeostasis", which found that IECs-driven mice require RIPK1/RIPK3
for gastrointestinal and systemic GVHD.
In addition to mediating necrosis, the RIPK1/RIPK3 and JAK1 complexes promote the activation of STAT1 in IECs, leading to a feed-forward inflammatory cascade of allogeneic T cell
responses.
Not only that, but this work also found a selective and potent RIPK1 inhibitor (Zharp1-211) that significantly reduces JAK/STAT1-mediated IEC inflammation, restores intestinal homeostasis, and inhibits GVHD
without affecting the anti-leukemia effect of grafts.
In conclusion, targeting RIPK1/RIPK3 in IECs is an effective non-immunosuppressive strategy for GVHD therapy and may be used for other diseases
involving gastrointestinal inflammation.
.
Some studies have shown that IEC presentation of MHC class II initiates the GVHD inflammatory cascade, while others have shown that intestinal epithelial cell inflammation-mediated cell death leads to severe GVHD
.
A better understanding of the molecular basis of IECs promoting GVHD could enable innovative therapeutic strategies
for managing inflammatory diseases in a broader context.
Receptor-interacting protein kinase (RIPK) 1 and RIPK3 are activators
of necrotic cell death.
Stimulated by inflammation, RIPK1 and RIPK3 are activated, and subsequently mixed lineage kinase domain-like protein (MLKL) is phosphorylated
.
Activated MLKL oligomerization, translocation to cell membranes and induction of necrosis
.
Necrosis is a form of inflammatory cell death that results in the release of damage-associated molecular patterns (DAMPs) to amplify the inflammatory response
.
Necrosis of small intestinal epithelial cells causes intestinal inflammation
.
Many causative factors, such as tumor necrosis factor (TNF), toll-like receptor (TLR) agonists, type I interferons, and viral infections, have been shown to activate RIPK3
.
These immunostimuli induce IEC necrosis
by inhibiting caspase-8 activity.
The absence of the autophagy protein ATG16L1 in IECs enhances the RIPK3-mediated effect
.
However, it remains unclear
whether targeting RIPK1/RIPK3 may lead to inhibition of intestinal inflammation and cell death in ATG16L1-sufficient hosts (i.
e.
, wild-type hosts).
The study reported that IECs after allogeneic hematopoietic stem cell transplantation require receptor-interacting protein kinase-3 (RIPK3) to drive gastrointestinal (GI) and systemic GVHD
.
GVHD
in the gut and liver of mice was significantly reduced by selectively inhibiting RIPK3 in IECs.
IECs RIPK3 works with RIPK1 to trigger the production of chemokines and MHC class II molecules independently of MLKL-recruited T cells that amplify and maintain the alloreactive response
of T cells.
Figure 1.
Deletion of RIPK3 in IECs can reduce local and systemic GVHD (Blood Source) Further studies have shown that IFN-γ produced by allogeneic T cells enhances the effect of RIPK1/RIPK3 in IECs through the JAK/STAT1-dependent mechanism, producing a feed-forward inflammatory cascade
.
RIPK1/RIPK3 and JAK1 complexes promote STAT1 activation
in IECs.
The inflammatory cascade of RIPK1/RIPK3-mediated allogeneic T cell responses leads to intestinal tissue damage, transforming local inflammation into systemic syndrome
.
Human patients with severe graft-versus-host disease show highly activated RIPK1
in the colonic epithelium.
Figure 2.
IFN-γ enhances the binding of RIPK1 to JAK1 and activates STAT1 in IECs (Blood Source) It is worth noting that the study found a selective and potent RIPK1 inhibitor (Zharp1-211) that significantly reduced the expression of JAK/STAT1-mediated chemokines and MHC class II molecules in IECs, restored intestinal homeostasis, and did not affect graft anti-leukemia ( Graft-versus-leukemia, GVL) effect in case of blocking GVHD
.
Figure 3.
Development of a novel RIPK1 kinase inhibitor (from Blood) In summary, the study revealed that the RIPK1/RIPK3 signaling pathway in IECs activates JAK1/STAT1-mediated chemokines and MHC II molecules and triggers an inflammatory cascade of allogeneic T cell
responses 。 In addition, the study found that Zharp1-211 selectively inhibits the activation of JAK1/STAT1 signaling by RIPK1 in IECs, which illustrates a unique strategy
for the treatment of graft-versus-host disease and other T cell-mediated inflammatory diseases such as inflammatory bowel disease.
This study demonstrates the concept of targeting RIPK1/RIPK3-regulated inflammatory responses in IECs as a non-immunosuppressive therapy for the prevention and treatment of
GVHD.
This paper opens new perspectives
for a better understanding of the molecular mechanisms that regulate RIPK1/RIPK3 signaling activation in epithelial cells, as well as their cell death-dependent and non-death functions that drive inflammation and immune responses.
Original link: https://doi.
org/10.
1182/blood.
2022017262
—END—
The content is [iNature]
