In This Issue

There is a strong association between inflammatory bowel disease (IBD) and primary sclerosing cholangitis (PSC) in the liver. Additionally, an imbalance between Foxp3⁺ regulatory T cells (Tregs) and Th17 cells is associated with both IBD and PSC. In this issue, Mathies et al. (p. 3558) investigated if intestinal inflammation and barrier defects promote liver disease. In two murine models, induction of colitis resulted in bacterial translocation to the liver and an influx of inflammatory cells, including Th17 cells. Although liver Tregs also were concomitantly increased in a dextran sodium sulfate (DSS) model of colitis, the authors did not observe overt signs of liver pathology in these animals. In contrast, induction of T cell–mediated colitis via transfer of differentiated Th17 cells into lymphopenic mice was associated with marked liver inflammation and pathology. Furthermore, depletion of Tregs in DSS-induced colitis promoted liver pathology, indicating a protective function for Tregs in this model. Finally, inflammatory cells, including CD4⁺ T cells, migrate from the colon into the liver during colitis. Together, these data demonstrate that colon-derived CD4⁺ T cells might be stimulated by the same microbial Ags they have been primed with in the intestine to drive liver pathology if not controlled by Foxp3⁺ Tregs.

Meteorin-like (Metrnl) is a small secreted protein (∼28 kDa) that is evolutionarily linked to the neurotropic factor Meteorin and has been shown to play a role in metabolic responses. Ushach et al. (p. 3669) now show that Metrnl, which they call Meteorin-β (Metrnβ), can function as an immunoregulatory cytokine. In vitro, macrophage secretion of Metrnβ was induced by TNF-α, and to a lesser degree with other cytokines, but IFN-γ and TGF-β treatment reduced Metrnβ levels. Inflammatory stimuli also induced Metrnβ production in LPS-treated macrophages and in a mouse model of sterile inflammation. Metrnβ treatment of macrophages induced an array of cytokines and chemokines. Metrnl^−/− mice showed normal growth and development but had multiple immune system abnormalities, including defects in Ig responses and altered cytokine and chemokine responses. In addition, Metrnl^−/− mice were more susceptible to LPS-induced sepsis, and older Metrnl^−/− mice spontaneously developed inflammatory lesions. Taken together, these results define Metrnβ as a cytokine in mice that is critical to regulating inflammatory responses.

The DNA sensor absent in melanoma 2 (AIM2) forms an inflammasome complex with ASC and caspase-1 resulting in the production of IL-1β and IL-18 and pyroptosis. Although AIM2 is critical for protection against Francisella tularensis subspecies novicida (F. novicida), the role of pyroptosis downstream of the AIM2 inflammasome is unknown. In this issue, Zhu et al. (p. 3662) demonstrated that mice lacking gasdermin D (GSDMD), the molecule executing pyroptosis downstream of caspase-1 and caspase-11 by forming pores on plasma membranes, had significantly increased F. novicida burden in the liver and spleen that correlated with a reduction in survival. Furthermore, GSDMD was critical for capsase-1 activation and pyropotic cell death in bone marrow–derived macrophages (BMDMs) infected with F. novicida. Consistent with these observations, GSDMD was required for caspase-1 activation in BMDMs by other inflammasome triggers such as poly(dA:dT) or murine CMV infection, indicating that GSDMD plays an important role in mediating pyroptosis after AIM2 activation. Finally, infection of BMDMs lacking AIM2 or ASC exhibited impaired cleavage of GSDMM. Together, these results highlight the critical role for GSDMD in promoting optimal caspase-1 activation and subsequent pyroptosis following AIM2 inflammasome triggers.

Effective CD8⁺ T cell responses against solid tumors are initiated through interactions with basic leucine zipper transcription factor ATF-like3 (Batf3)-lineage dendritic cells (DCs) that present tumor Ags, but less is known about how these DCs influence CD8⁺ T cell responses against leukemias. In this issue, Kline et al. (p. 3759) show that CD8α⁺ DCs can selectively acquire and cross-present leukemia Ag, which results in tolerogenic CD8⁺ T cell responses in a mouse model of this cancer. Uptake of leukemia Ags triggers a specific transcriptional profile in CD8α⁺ DCs that was associated with a tolerogenic phenotype. In contrast, TLR3-mediated activation of CD8α⁺ DCs prevents induction of CD8⁺ T cell tolerance and is associated with antileukemia responses and improved survival. These findings suggest that Batf3-lineage DCs may have different antitumor CD8⁺ T cell responses against solid tumors or leukemias.

Inflammatory bowel disease (IBD) describes disorders that are associated with chronic inflammation of the digestive tract. Current therapies include suppressing inflammatory responses and restoring immune tolerance in the gut, but many of these treatments do not work in the long term. Aoki et al. (p. 3683) examined the role of aryl hydrocarbon receptor (AHR), a transcription factor known to be involved in maintaining homeostasis in the gut mucosa, in impairing colitis pathogenesis. The aromatic pyruvic acid indole-3-pyruvic acid (IPA) is a known precursor of AHR agonists, and in this article, the authors show that IPA can activate AHR in vitro and in a mouse model of T cell–mediated colitis. IPA treatment reduced colonic inflammation and was associated with a reduced frequency of Th1 cells and an increased frequency of type 1 regulatory T cells in the colon. IPA also increased the frequency of CD103⁺CD11b⁻ dendritic cells in mesenteric lymph nodes, and adoptive transfer of these cells into mice reduced colitis severity. Together, these results suggest that IPA can attenuate colitis severity by activating AHR.