Host NLRP6 exacerbates graft-versus-host disease independent of microbial diversity
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ABSTRACT: Host NLRP6 regulates innate immune responses and gastrointestinal (GI) homeostasis. It plays a protective role in pathogenic processes such as intestinal colitis and tumorigenesis in a microbiome dependent manner. Host innate immunity and changes in microbial diversity also play a role in the severity of allo-immune-mediated gastrointestinal pathogenic process, namely graft-versus-host disease (GVHD), the principal toxicity after allogeneic bone marrow transplantation (allo-BMT). Herein, we examined the role of NLRP6 in multiple murine models of allo-BMT. In contrast to its role in intestinal colitis, host NLRP6 aggravated GI GVHD. NLRP6-deficient animals showed improved intestinal barrier function, increased levels of tissue repair associated proteins and preserved Goblet and Paneth cell numbers in the GI tract after allo-BMT. The impact of host NLRP6 deficiency in mitigating GVHD was observed regardless of co-housing, antibiotic treatment, or colonizing littermate germ free wild type (WT) and NLRP6 deficient hosts with fecal microbial transplantation from SPF WT and Nlrp6-/- animals. Chimera studies were performed to assess the role of NLRP6 expression on host hematopoietic and non-hematopoietic cells. The allogeneic [B6Ly5.2→Nlrp6-/-] animals demonstrated significantly improved survival compared to the allogeneic [B6Ly5.2→B6] animals, demonstrating that the absence of NLRP6 in host non-hematopoietic cells is crucial for the protection against GVHD, but did not alter the therapeutic graft-versus-tumor effects after BMT. Our results unveil a novel role for NLRP6 and demonstrate a pathogenic role in GVHD that is independent of variations in its intestinal microbiome in contrast to its well-appreciated microbiome-dependent protective role in intestinal colitis and tumorigenesis.
ORGANISM(S): Mouse Mus Musculus
TISSUE(S): Intestine
SUBMITTER: Anna Mathew
PROVIDER: ST001089 | MetabolomicsWorkbench | Mon Nov 05 00:00:00 GMT 2018
REPOSITORIES: MetabolomicsWorkbench
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