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    • br Results br Discussion Mucosal barriers are constitutively

    2020-10-27


    Results
    Discussion Mucosal barriers are constitutively challenged by various stimuli, and the homeostasis of mucosal barriers both at steady state and upon challenge are maintained by tissue-resident immune Bialaphos sodium salt (Kurashima et al., 2013, Okumura and Takeda, 2016). ILC3s are found in lymphoid tissues and are enriched in the intestine, where they play critical roles in regulating adaptive immune responses against commensal bacteria, as well as in innate immunity against enteric bacterial infections (Hepworth et al., 2013, Hepworth et al., 2015, Rankin et al., 2016, Satoh-Takayama et al., 2008, Sawa et al., 2011, Song et al., 2015, Sonnenberg et al., 2011). Although the mechanisms ILC3s employ to control infections and promote tissue repair continue to be defined (Satoh-Takayama et al., 2008, Sawa et al., 2011, Sonnenberg et al., 2011), our understanding of how the accumulation, distribution, and tissue-protective function of ILC3s in the intestine and its associated lymphoid organs are controlled remained limited. Emgård et al. (2018) recently reported that CD4+ LTi-like ILC3s express GPR183 that controls cell migration and formation of solitary intestinal lymphoid tissues in the colon and enhances IL-22 production by ILC3s in the colon at steady state. In the current study, we demonstrate that GPR183 is expressed on murine and human ILC3s and that GPR183 and its ligand 7α,25-OHC regulate the accumulation and distribution of ILC3s in lymphoid tissues and the intestine, and consequently, GPR183 controls ILC3-dependent innate immunity and tissue protection following enteric bacterial infection. We also identify GPR183-dependent accumulation of IL-22-producing ILC3s in the intestine following C. rodentium infection. Of note, enhanced IL-22 production by ILC3s was not detectable, possibly due to heightened inflammation elicited by the bacterial infection. ILC3s reside in the interfollicular areas of the mLNs, where they present commensal bacterial antigen through major histocompatibility complex class II and prevent CD4+ T cell-induced chronic intestinal inflammation toward commensal bacteria (Hepworth et al., 2015). In this study, we show that GPR183 controls the distribution of ILC3s in mLNs. GPR183-deficient ILC3s accumulated in the outer regions of the interfollicular areas, which are close to the subcapsular sinuses. DCs migrate into the LNs via the lymph through subcapsular sinuses and then move to the paracortex where they interact with helper T cells (Lian and Luster, 2015). This pathway is regulated by CCR7, a molecule that also controls the accumulation of ILC3s to LNs (Lian and Luster, 2015, Mackley et al., 2015). Similarly, ILC3s migrate from other organs, such as the intestine (Mackley et al., 2015), and enter the LNs through subcapsular sinuses. In the context of GPR183 deficiency, ILC3s cannot migrate into the interfollicular areas because they fail to respond to the ligand expressed in the inner regions of the interfollicular areas and hence are sequestered in the subcapsular sinuses. As GPR183 plays such important roles in regulating the distribution and function of ILC3s in both lymphoid and non-lymphoid tissues, GPR183 itself and its oxysterol ligand-producing pathway could be potential therapeutic targets for controlling and regulating ILC3 functions in multiple infectious and inflammatory diseases.
    Experimental Procedures Further details and an outline of resources used in this work can be found in Supplemental Experimental Procedures.
    Introduction Oxysterols came to prominence in the late 1970\'s with the oxysterol hypothesis which proposed that the suppressive effect of cholesterol on its own synthesis is mediated through oxysterols not by cholesterol itself [1]. This has proved to be only partly true, as cholesterol homeostasis in cells is modulated through oxysterols, side-chain oxysterols inhibiting the SREBP2 (sterol regulatory element-binding protein 2) pathway and also activating liver X receptors (LXRs) [2,3], although cholesterol itself is in fact the major regulator of its own synthesis through binding to SCAP (SREBP cleavage activating protein) and preventing transport of SERBP2 from the endoplasmic reticulum for processing to its active form as a transcription factor for genes of the cholesterol biosynthesis pathway [4]. In recent years oxysterols have been shown to have important functions in immunology [[5], [6], [7], [8], [9], [10], [11], [12], [13]], development [14,15] and cancer [[16], [17], [18], [19], [20]]. This has stimulated wide-spread interest in their analysis using lipidomics technology [21,22]. Although mostly thought of as oxidised forms of cholesterols, oxysterols can also be formed from precursors of cholesterol greatly widening the range of molecules required to be analysed in a lipidomic study.