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BackgroundThe IL-17 family cytokines are potent drivers of colorectal cancer (CRC) development. We and others have shown that IL-17 mainly signals to tumor cells to promote CRC, but the underlying mechanism remains unclear. IL-17 also dampens Th1-armed anti-tumor immunity, in part by attracting myeloid cells to tumor. Whether IL-17 controls the activity of adaptive immune cells in a more direct manner, however, is unknown.MethodsUsing mouse models of sporadic or inducible colorectal cancers, we ablated IL-17RA in the whole body or specifically in colorectal tumor cells. We also performed adoptive bone marrow reconstitution to knockout CXCR3 in hematopoietic cells. Histological and immunological experimental methods were used to reveal the link among IL-17, chemokine production, and CRC development.ResultsLoss of IL-17 signaling in mouse CRC resulted in marked increase in the recruitment of CD8+ cytotoxic T lymphocytes (CTLs) and regulatory T cells (Tregs), starting from early stage CRC lesions. This is accompanied by the increased expression of anti-inflammatory cytokines IL-10 and TGF-β. IL-17 signaling also inhibits the production of T cell attracting chemokines CXCL9 and CXCL10 by tumor cells. Conversely, the inability of hematopoietic cells to respond to CXCL9/10 resulted in decreased tumor infiltration by CTLs and Tregs, decreased levels of IL-10 and TGF-β, and increased numbers of tumor lesions. Blockade of IL-17 signaling resulted in increased expression of immune checkpoint markers. On the other hand, treatment of mouse CRC with anti-CTLA-4 antibody led to increased expression of pro-tumor IL-17.ConclusionIL-17 signals to colorectal tumor cells and inhibits their production of CXCL9/10 chemokines. By doing so, IL-17 inhibits the infiltration of CD8+ CTLs and Tregs to CRC, thus promoting CRC development. Cancer immunotherapy may be benefited by the use of anti-IL-17 agents as adjuvant therapies, which serve to block both IL-17-mediated tumor promotion and T cell exclusion.

Sleep is an essential behavioral state of rest that is regulated by homeostatic drives to ensure a balance of sleep and activity, as well as independent arousal mechanisms in the central brain. Dopamine has been identified as a critical regulator of both sleep behavior and arousal. Here, we present results of a genetic screen that selectively restored the Dopamine Receptor (DopR/DopR1/dumb) to specific neuroanatomical regions of the adult Drosophila brain to assess requirements for DopR in sleep behavior. We have identified subsets of the mushroom body that utilizes DopR in daytime sleep regulation. These data are supported by multiple examples of spatially restricted genetic rescue data in discrete circuits of the mushroom body, as well as immunohistochemistry that corroborates the localization of DopR protein within mushroom body circuits. Independent loss of function data using an inducible RNAi construct in the same specific circuits also supports a requirement for DopR in daytime sleep. Additional circuit activation of discrete DopR+ mushroom body neurons also suggests roles for these subpopulations in sleep behavior. These conclusions support a new separable function for DopR in daytime sleep regulation within the mushroom body. This daytime regulation is independent of the known role of DopR in nighttime sleep, which is regulated within the Fan-Shaped Body (FSB). This study provides new neuroanatomical loci for exploration of dopaminergic sleep functions in Drosophila, and expands our understanding of sleep regulation during the day vs. night.

Drosophila groom away debris and pathogens from the body using their legs in a stereotyped sequence of innate motor behaviors. Here, we investigated one aspect of the grooming repertoire by characterizing the D1 family dopamine receptor, DopR. Removal of DopR results in decreased hind leg grooming, as substantiated by quantitation of dye remaining on mutant and RNAi animals vs. controls and direct scoring of behavioral events. These data are also supported by pharmacological results that D1 receptor agonists fail to potentiate grooming behaviors in headless DopR flies. DopR protein is broadly expressed in the neuropil of the thoracic ganglion and overlaps with TH‐positive dopaminergic neurons. Broad neuronal expression of dopamine receptor in mutant animals restored normal grooming behaviors. These data provide evidence for the role of DopR in potentiating hind leg grooming behaviors in the thoracic ganglion of adult Drosophila. This is a remarkable juxtaposition to the considerable role of D1 family dopamine receptors in rodent grooming, and future investigations of evolutionary relationships of circuitry may be warranted.

In this study, we demonstrate that correcting the monocyte adhesion defect in CFTR ΔF508 mice (CF mice) by bone marrow transplantation significantly improved survival and reduced inflammation.

The consumption of processed foods and sugary sodas in Western diets correlates with an increased incidence of obesity, metabolic syndromes such as type 2 diabetes, cardiovascular diseases, and autoimmune diseases including inflammatory bowel disease and rheumatoid arthritis. All these diseases have an inflammatory component, of which T lymphocytes can play a critical role in driving. Much has been learned regarding the importance of sugar, particularly glucose, in fueling effector versus regulatory T cells that can promote or dampen inflammation, respectively. In particular, glucose and its metabolic breakdown products via glycolysis are essential for effector T cell differentiation and function, while fatty acid-fueled oxidative phosphorylation supports homeostasis and function of regulatory T cells. Nevertheless, a critical knowledge gap, given the prevalence of diabetes in Western societies, is the impact of elevated glucose concentrations on the balance between effector versus regulatory T cells. To begin addressing this, we cultured naïve CD4+ T cells with different concentrations of glucose, and examined their differentiation into effector versus regulatory lineages. Surprisingly, high glucose promoted regulatory T cell differentiation and inhibited Th1 effector differentiation. This skewing towards the regulatory lineage occurred via an indirect mechanism that depends on lactate produced by activated glycolytic T cells. Addition of lactate to the T cell differentiation process promotes the differentiation of Treg cells, and activates Akt/mTOR signaling cascade. Hence, our findings suggest the existence of a novel feedback mechanism in which lactate produced by activated, differentiating T cells skews their lineage commitment towards the regulatory fate.

Inflammatory bowel diseases are rising in prevalence globally. While current treatments aim to achieve remission, there remains no cure for this disease. IL-17 family cytokines are important players in inflammation, but clinical trials using anti-IL-17A or IL-17RA blocking antibodies have failed for Crohn’s disease, due to exacerbated inflammation in some patients. While anti-IL-17 antibodies have shown efficacy in the treatment of other autoimmune diseases like psoriasis, patients can often develop Crohn’s disease as a side effect of these drugs. These data suggest a protective role of IL-17 in gut inflammation. The proper activation and function of regulatory T cells is essential for the protection against intestinal autoimmune inflammation. Using the naïve T cell transfer model of colitis in mice, we found that IL-17RA-null iTregs, transferred after the establishment of colitis, were less effective at controlling the colitis compared to WT iTregs. Naïve T cells cultured ex vivo in iTreg polarizing conditions had an increase in complete iTreg differentiation when stimulated with IL-17 cytokines. Our results indicate that IL-17 directly signals to Tregs and assists their anti-inflammatory role during autoimmune gut inflammation. Although the underlying mechanism remains under study, this finding suggests an inhibitory loop between IL-17 and Tregs for the control of overt inflammation.