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Publication
Host NLRP6 exacerbates graft-versus-host disease independent of gut microbial
composition.
Authors Toubai T, Fujiwara H, Rossi C, Riwes M, Tamaki H, Zajac C, Liu C, Mathew AV,
Byun J, Oravecz-Wilson K, Matsuda I, Sun Y, Peltier D, Wu J, Chen J, Seregin S,
Henig I, Kim S, Brabbs S, Pennathur S, Chen G, Reddy P
Submitted By Submitted Externally on 4/30/2020
Status Published
Journal Nature microbiology
Year 2019
Date Published 5/1/2019
Volume : Pages 4 : 800 - 812
PubMed Reference 30858572
Abstract Host NOD-like receptor family pyrin domain-containing 6 (NLRP6) regulates innate
immune responses and gastrointestinal homeostasis. Its protective role in
intestinal colitis and tumorigenesis is dependent on the host microbiome. Host
innate immunity and microbial diversity also play a role in the severity of
allogeneic immune-mediated gastrointestinal graft-versus-host disease (GVHD),
the principal toxicity after allogeneic haematopoietic cell transplantation.
Here, we examined the role of host NLRP6 in multiple murine models of allogeneic
bone marrow transplantation. In contrast to its role in intestinal colitis, host
NLRP6 aggravated gastrointestinal GVHD. The impact of host NLRP6 deficiency in
mitigating GVHD was observed regardless of co-housing, antibiotic treatment or
colonizing littermate germ-free wild-type and NLRP6-deficient hosts with faecal
microbial transplantation from specific pathogen-free wild-type and Nlrp6-/-
animals. Chimaera studies were performed to assess the role of NLRP6 expression
on host haematopoietic and non-haematopoietic cells. The allogeneic
[B6Ly5.2???Nlrp6-/-] animals demonstrated significantly improved survival
compared to the allogeneic [B6Ly5.2???B6] animals, but did not alter the
therapeutic graft-versus-tumour effects after haematopoietic cell
transplantation. Our results unveil an unexpected, pathogenic role for host
NLRP6 in gastrointestinal GVHD that is independent of variations in the
intestinal microbiome and in contrast to its well-appreciated
microbiome-dependent protective role in intestinal colitis and tumorigenesis.




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