Mario Noti

TSLP Elicits IL-33–Independent Innate Lymphoid Cell Responses to Promote Skin Inflammation

Group 2 innate lymphoid cells are essential to the pathogenesis of atopic dermatitis–like disease in a TSLP-dependent, IL-33–independent manner. Immune Cell Activity at the Skin Barrier The skin acts like soft armor, protecting the body from disease and environmental insults. In atopic dermatitis (AD), this barrier is disrupted, leading to inflammation. The role of various immune cells in this chronic disease has not been clear. Now, Kim and colleagues identify a subset of innate lymphoid cells (ILCs) in both human and mouse skin that contribute to disease pathogenesis. ILCs have been reported in inflamed nasal polyps in people, as well as in inflamed lungs in mice. Hypothesizing that they also play a role in skin inflammation, Kim et al. analyzed cells isolated from the skin tissue of healthy control subjects and from the lesions of AD patients. There were more Lin− CD25+ IL-33R+ RORγt− group 2 ILCs (ILC2s) in the lesions of AD patients. In healthy mouse skin, the authors identified a similar ILC2 population. AD in humans is linked to cytokines interleukin-33 (IL-33), IL-25, and thymic stromal lymphopoietin (TSLP) in the skin. To this end, the authors investigated in mice whether the ILC2s played a role in inflammation at the skin barrier and if they were dependent on these cytokines. In a mouse model of AD, Kim et al. noted that ILC2s were increased and that AD pathogenesis was initiated independently of adaptive immunity and RORγt+ cells (a marker of group 3 ILCs). The mechanism was also independent of IL-25 and IL-33—which are normally implicated in group 2 ILC responses—yet dependent on TSLP. Depletion of the ILCs attenuated AD-like dermatitis in mice. Group 2 ILCs have not yet been described in skin barrier function in humans. In these studies, Kim and colleagues show that ILC2s are always present in healthy skin, but accumulate in AD lesions and function by a mechanism that contrasts what has been reported in lungs and intestine. Future functional studies will be needed for human ILC2s in skin inflammation, but these preliminary data in mice and humans suggest that targeting group 2 ILCs will be a viable target for treating AD and other allergic diseases. Innate lymphoid cells (ILCs) are a recently identified family of heterogeneous immune cells that can be divided into three groups based on their differential developmental requirements and expression of effector cytokines. Among these, group 2 ILCs produce the type 2 cytokines interleukin-5 (IL-5) and IL-13 and promote type 2 inflammation in the lung and intestine. However, whether group 2 ILCs reside in the skin and contribute to skin inflammation has not been characterized. We identify a population of skin-resident group 2 ILCs present in healthy human skin that are enriched in lesional human skin from atopic dermatitis (AD) patients. Group 2 ILCs were also found in normal murine skin and were critical for the development of inflammation in a murine model of AD-like disease. Remarkably, in contrast to group 2 ILC responses in the intestine and lung, which are critically regulated by IL-33 and IL-25, group 2 ILC responses in the skin and skin-draining lymph nodes were independent of these canonical cytokines but were critically dependent on thymic stromal lymphopoietin (TSLP). Collectively, these results demonstrate an essential role for IL-33– and IL-25–independent group 2 ILCs in promoting skin inflammation.

Thymic stromal lymphopoietin–elicited basophil responses promote eosinophilic esophagitis

Eosinophilic esophagitis (EoE) is a food allergy–associated inflammatory disease characterized by esophageal eosinophilia. Current management strategies for EoE are nonspecific, and thus there is a need to identify specific immunological pathways that could be targeted to treat this disease. EoE is associated with polymorphisms in the gene that encodes thymic stromal lymphopoietin (TSLP), a cytokine that promotes allergic inflammation, but how TSLP might contribute to EoE disease pathogenesis has been unclear. Here, we describe a new mouse model of EoE-like disease that developed independently of IgE, but was dependent on TSLP and basophils, as targeting TSLP or basophils during the sensitization phase limited disease. Notably, therapeutic TSLP neutralization or basophil depletion also ameliorated established EoE-like disease. In human subjects with EoE, we observed elevated TSLP expression and exaggerated basophil responses in esophageal biopsies, and a gain-of-function TSLP polymorphism was associated with increased basophil responses in patients with EoE. Together, these data suggest that the TSLP-basophil axis contributes to the pathogenesis of EoE and could be therapeutically targeted to treat this disease.

Innate immune cell populations function as initiators and effectors in Th2 cytokine responses

The recent identification of previously unrecognized innate cell populations, termed natural helper cells (NHCs), multi-potent progenitor type 2 (MPP(type2)) cells, nuocytes, and innate type 2 helper (Ih2) cells has provided new insights into our understanding of the cellular mechanisms that lead to the development of CD4(+) Th2 cell-dependent immunity and/or inflammation at mucosal sites. In this review, we focus on the functional significance, similarities, and differences between NHCs, MPP(type2) cells, nuocytes and Ih2 cells. All four cell populations are activated by interleukin (IL)-25 and/or IL-33 and are capable of promoting Th2 cytokine responses. Collectively, the identification of these cell populations might illuminate ancient evolutionary conserved pathways that are involved in the development of Th2 cytokine responses, and could be of benefit in the development of therapeutic approaches that target helminth infections and allergic diseases.

IL-33 promotes an innate immune pathway of intestinal tissue protection dependent on amphiregulin–EGFR interactions

Significance Mammalian barrier surfaces are exposed to environmental stimuli that can result in tissue damage. Interleukin (IL)-33–dependent group 2 innate lymphoid cells (ILC2s) are enriched at barrier sites, but the mechanisms underlying the tissue-protective roles of IL-33 or ILC2s in the intestine remain poorly defined. Here we use a model of murine intestinal inflammation and reveal a previously unrecognized pathway of innate immune cell-mediated tissue protection in which IL-33 ameliorated disease through induction of ILC2s and the growth factor amphiregulin (AREG). Collectively, these data highlight a critical dialogue between damaged epithelia and innate immune cells and indicate that manipulation of the IL-33–ILC2–AREG pathway could provide therapeutic benefit in treatment of intestinal inflammatory diseases. The barrier surfaces of the skin, lung, and intestine are constantly exposed to environmental stimuli that can result in inflammation and tissue damage. Interleukin (IL)-33–dependent group 2 innate lymphoid cells (ILC2s) are enriched at barrier surfaces and have been implicated in promoting inflammation; however, the mechanisms underlying the tissue-protective roles of IL-33 or ILC2s at surfaces such as the intestine remain poorly defined. Here we demonstrate that, following activation with IL-33, expression of the growth factor amphiregulin (AREG) is a dominant functional signature of gut-associated ILC2s. In the context of a murine model of intestinal damage and inflammation, the frequency and number of AREG-expressing ILC2s increases following intestinal injury and genetic disruption of the endogenous AREG–epidermal growth factor receptor (EGFR) pathway exacerbated disease. Administration of exogenous AREG limited intestinal inflammation and decreased disease severity in both lymphocyte-sufficient and lymphocyte-deficient mice, revealing a previously unrecognized innate immune mechanism of intestinal tissue protection. Furthermore, treatment with IL-33 or transfer of ILC2s ameliorated intestinal disease severity in an AREG-dependent manner. Collectively, these data reveal a critical feedback loop in which cytokine cues from damaged epithelia activate innate immune cells to express growth factors essential for ILC-dependent restoration of epithelial barrier function and maintenance of tissue homeostasis.

Basophils Promote Innate Lymphoid Cell Responses in Inflamed Skin

Type 2 inflammation underlies allergic diseases such as atopic dermatitis, which is characterized by the accumulation of basophils and group 2 innate lymphoid cells (ILC2s) in inflamed skin lesions. Although murine studies have demonstrated that cutaneous basophil and ILC2 responses are dependent on thymic stromal lymphopoietin, whether these cell populations interact to regulate the development of cutaneous type 2 inflammation is poorly defined. In this study, we identify that basophils and ILC2s significantly accumulate in inflamed human and murine skin and form clusters not observed in control skin. We demonstrate that murine basophil responses precede ILC2 responses and that basophils are the dominant IL-4–enhanced GFP-expressing cell type in inflamed skin. Furthermore, basophils and IL-4 were necessary for the optimal accumulation of ILC2s and induction of atopic dermatitis–like disease. We show that ILC2s express IL-4Rα and proliferate in an IL-4–dependent manner. Additionally, basophil-derived IL-4 was required for cutaneous ILC2 responses in vivo and directly regulated ILC2 proliferation ex vivo. Collectively, these data reveal a previously unrecognized role for basophil-derived IL-4 in promoting ILC2 responses during cutaneous inflammation.

TNF suppresses acute intestinal inflammation by inducing local glucocorticoid synthesis

Although tumor necrosis factor (α) (TNF) exerts proinflammatory activities in a variety of diseases, including inflammatory bowel disease, there is increasing evidence for antiinflammatory actions of TNF. In contrast, glucocorticoids (GCs) are steroid hormones that suppress inflammation, at least in part by regulating the expression and action of TNF. We report that TNF induces extraadrenal production of immunoregulatory GCs in the intestinal mucosa during acute intestinal inflammation. The absence of TNF results in a lack of colonic GC synthesis and exacerbation of dextran sodium sulfate–induced colitis. TNF seems to promote local steroidogenesis by directly inducing steroidogenic enzymes in intestinal epithelial cells. Therapeutic administration of TNF induces GC synthesis in oxazolone-induced colitis and ameliorates intestinal inflammation, whereas inhibition of intestinal GC synthesis abrogates the therapeutic effect of TNF. These data show that TNF suppresses the pathogenesis of acute intestinal inflammation by promoting local steroidogenesis.

The nuclear receptor LRH-1 critically regulates extra-adrenal glucocorticoid synthesis in the intestine

The nuclear receptor liver receptor homologue-1 (LRH-1, NR5A2) is a crucial transcriptional regulator of many metabolic pathways. In addition, LRH-1 is expressed in intestinal crypt cells where it regulates the epithelial cell renewal and contributes to tumorigenesis through the induction of cell cycle proteins. We have recently identified the intestinal epithelium as an important extra-adrenal source of immunoregulatory glucocorticoids. We show here that LRH-1 promotes the expression of the steroidogenic enzymes and the synthesis of corticosterone in murine intestinal epithelial cells in vitro. Interestingly, LRH-1 is also essential for intestinal glucocorticoid synthesis in vivo, as LRH-1 haplo-insufficiency strongly reduces the intestinal expression of steroidogenic enzymes and glucocorticoid synthesis upon immunological stress. These results demonstrate for the first time a novel role for LRH-1 in the regulation of intestinal glucocorticoid synthesis and propose LRH-1 as an important regulator of intestinal tissue integrity and immune homeostasis.

Epithelial-intrinsic IKKα expression regulates group 3 innate lymphoid cell responses and antibacterial immunity

Expression of IKKα in intestinal epithelial cells promotes IL-22 production by group 3 innate lymphoid cells, and this axis is essential for defense against Citrobacter rodentium infection and to limit intestinal inflammation in response to DSS treatment.

Dry roasting enhances peanut-induced allergic sensitization across mucosal and cutaneous routes in mice

the HPV cohort. This could have introduced an ascertainment bias for HPV detection and may explain our lower overall rate of identified HPV. However, it is clear that post-HSCT, the cohort without HPV disease had markedly improved NK cell engraftment when compared with their counterparts with HPV disease. Investigators have proposed that in gc receptor deficiency, dendritic cells may remain dysfunctional post-HSCT and thus permissive toHPVinfection despite donorT cell engraftment.No specific data supports this theory. Our study revealed a lower incidence of HPV disease than in other cohorts, likely related to the lowermean age of ourHPV-negative cohort and excellent engraftment of T, B, and NK cells in our entire cohort. We propose that poor NK cell engraftment and function represents a more likely contributor to the development of severe HPV disease in our 4 patients. It is possible that pre-HSCT myeloablation improved NK cell engraftment and function, allowing for improved response to HPVexposure in later life and thus disease limitation. With improvements in early diagnosis and curative treatment in SCID, it is imperative to review and determine the etiology of long-term adverse events like severe HPV disease following transplant.

Extra-adrenal glucocorticoid synthesis in the intestinal epithelium: more than a drop in the ocean?

Glucocorticoids (GC) are lipophilic hormones commonly used as therapeutics in acute and chronic inflammatory disorders such as inflammatory bowel disease due to their attributed anti-inflammatory and immunosuppressive actions. Although the adrenal glands are the major source of endogenous GC, there is increasing evidence for the production of extra-adrenal GC in the brain, thymus, skin, vasculature, and the intestine. However, the physiological relevance of extra-adrenal-produced GC remains still ambiguous. Therefore, this review attracts attention to discuss possible biological benefits of extra-adrenal-synthesized GC, especially focusing on the impact of locally synthesized GC in the regulation of intestinal immune responses.