VIP-producing enteric neurons interact with innate lymphoid cells to regulate feeding-dependent intestinal epithelial barrier functions

ABSTRACTThe intestinal mucosa serves as both a conduit for uptake of food-derived nutrients and microbiome-derived metabolites and as a barrier that prevents tissue invasion by microbes and tempers inflammatory responses to the myriad contents of the lumen. How the intestine coordinates physiological and immune responses to food consumption to optimize nutrient uptake while maintaining barrier functions remains unclear. Here, we describe how a gut neuronal signal triggered by food intake is integrated with intestinal antimicrobial and metabolic responses controlled by type 3 innate lymphoid cells (ILC3)1-3. Food consumption rapidly activates a population of enteric neurons that express vasoactive intestinal peptide (VIP)4. Projections of VIP-producing neurons (VIPergic neurons) in the lamina propria are in close proximity to clusters of ILC3 that selectively express VIP receptor type 2 (VIPR2 or VPAC2). ILC3 production of IL-22, which is up-regulated by commensal microbes such as segmented filamentous bacteria (SFB)5-7, is inhibited upon engagement of VIPR2. As a consequence, there is a reduction in epithelial cell-derived antimicrobial peptide, but enhanced expression of lipid-binding proteins and transporters8. During food consumption, activation of VIPergic neurons thus enhances growth of epithelial-associated SFB and increases lipid absorption. Our results reveal a feeding- and circadian-regulated dynamic intestinal neuro-immune circuit that promotes a trade-off between IL-22-mediated innate immune protection and efficiency of nutrient absorption. Modulation of this pathway may hence be effective for enhancing resistance to enteropathogen2,3,9 and for treatment of metabolic diseases.

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Group 2 Innate Lymphoid Cells: Central Players in a Recurring Theme of Repair and Regeneration

International Journal of Molecular Sciences ◽

10.3390/ijms21041350 ◽

2020 ◽

Vol 21 (4) ◽

pp. 1350 ◽

Cited By ~ 3

Author(s):

Melina Messing ◽

Sia Cecilia Jan-Abu ◽

Kelly McNagny

Keyword(s):

T Regulatory Cells ◽

Inflammatory Responses ◽

Expression Profiles ◽

Innate Lymphoid Cells ◽

Lymphoid Cells ◽

Helminth Infections ◽

Neonatal Immunity ◽

Group 2 ◽

Transcription Factor Expression

Innate lymphoid cells (ILCs) are recently discovered innate counterparts to the well-established T helper cell subsets and are most abundant at barrier surfaces, where they participate in tissue homeostasis and inflammatory responses against invading pathogens. Group 2 innate lymphoid cells (ILC2s) share cytokine and transcription factor expression profiles with type-2 helper T cells and are primarily associated with immune responses against allergens and helminth infections. Emerging data, however, suggests that ILC2s are also key regulators in other inflammatory settings; both in a beneficial context, such as the establishment of neonatal immunity, tissue repair, and homeostasis, and in the context of pathological tissue damage and disease, such as fibrosis development. This review focuses on the interactions of ILC2s with stromal cells, eosinophils, macrophages, and T regulatory cells that are common to the different settings in which type-2 immunity has been explored. We further discuss how an understanding of these interactions can reveal new avenues of therapeutic tissue regeneration, where the role of ILC2s is yet to be fully established.

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Microbiota instruct IL-17A-producing innate lymphoid cells to promote skin inflammation in cutaneous leishmaniasis

10.1101/2021.06.08.447514 ◽

2021 ◽

Author(s):

Tej Pratap Singh ◽

Augusto Carvalho ◽

Elizabeth Grice ◽

Phillip Scott

Keyword(s):

Cutaneous Leishmaniasis ◽

Staphylococcus Epidermidis ◽

Leishmania Major ◽

Inflammatory Responses ◽

Skin Inflammation ◽

Innate Lymphoid Cells ◽

Lymphoid Cells ◽

Skin Microbiota ◽

Infected Skin

p.p1 {margin: 0.0px 0.0px 0.0px 0.0px; font: 12.0px Helvetica} span.s1 {color: #222222} span.s2 {font: 8.0px Helvetica} Innate lymphoid cells (ILCs) comprise a heterogeneous population of immune cells that maintain barrier function and can initiate a protective or pathological immune response upon infection. Here we show the involvement of IL-17A-producing ILCs in microbiota-driven immunopathology in cutaneous leishmaniasis. IL-17A-producing ILCs were RORgt + and were enriched in Leishmania major infected skin, and topical colonization with Staphylococcus epidermidis before L. major infection exacerbated the skin inflammatory responses and IL-17A-producing RORgt + ILC accumulation without impacting type 1 immune responses. IL-17A responses in ILCs were directed by Batf3 dependent CD103 + dendritic cells, and experiments using ILC deficient Rag1 -/- mice established that IL-17A + ILCs were sufficient in driving the inflammatory responses. As depletion of ILCs or neutralization of IL-17A diminished the microbiota mediated immunopathology. Taken together, this study indicates that the skin microbiota promotes RORgt + IL-17A-producing ILCs, which augment the skin inflammation in cutaneous leishmaniasis.

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Androgen signaling negatively controls group 2 innate lymphoid cells

Journal of Experimental Medicine ◽

10.1084/jem.20161807 ◽

2017 ◽

Vol 214 (6) ◽

pp. 1581-1592 ◽

Cited By ~ 95

Author(s):

Sophie Laffont ◽

Eve Blanquart ◽

Magali Savignac ◽

Claire Cénac ◽

Gilles Laverny ◽

...

Keyword(s):

Airway Inflammation ◽

Lung Inflammation ◽

Inflammatory Responses ◽

Allergic Airway Inflammation ◽

Innate Lymphoid Cells ◽

Protective Role ◽

Lymphoid Cells ◽

Peripheral Tissues ◽

Group 2

Prevalence of asthma is higher in women than in men, but the mechanisms underlying this sex bias are unknown. Group 2 innate lymphoid cells (ILC2s) are key regulators of type 2 inflammatory responses. Here, we show that ILC2 development is greatly influenced by male sex hormones. Male mice have reduced numbers of ILC2 progenitors (ILC2Ps) and mature ILC2s in peripheral tissues compared with females. In consequence, males exhibit reduced susceptibility to allergic airway inflammation in response to environmental allergens and less severe IL-33–driven lung inflammation, correlating with an impaired expansion of lung ILC2s. Importantly, orchiectomy, but not ovariectomy, abolishes the sex differences in ILC2 development and restores IL-33–mediated lung inflammation. ILC2Ps express the androgen receptor (AR), and AR signaling inhibits their differentiation into mature ILC2s. Finally, we show that hematopoietic AR expression limits IL-33–driven lung inflammation through a cell-intrinsic inhibition of ILC2 expansion. Thus, androgens play a crucial protective role in type 2 airway inflammation by negatively regulating ILC2 homeostasis, thereby limiting their capacity to expand locally in response to IL-33.

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T-Bet Controls Cellularity of Intestinal Group 3 Innate Lymphoid Cells

Frontiers in Immunology ◽

10.3389/fimmu.2020.623324 ◽

2021 ◽

Vol 11 ◽

Author(s):

Jan-Hendrik Schroeder ◽

Katrin Meissl ◽

Dominika Hromadová ◽

Jonathan W. Lo ◽

Joana F. Neves ◽

...

Keyword(s):

Critical Factor ◽

Innate Lymphoid Cells ◽

Lymphoid Cells ◽

Mucosal Surfaces ◽

Specific Pathogen ◽

Enhanced Expression ◽

Group 3 ◽

Deficient Mice

Innate lymphoid cells (ILC) play a significant immunological role at mucosal surfaces such as the intestine. T-bet-expressing group 1 innate lymphoid cells (ILC1) are believed to play a substantial role in inflammatory bowel disease (IBD). However, a role of T-bet-negative ILC3 in driving colitis has also been suggested in mouse models questioning T-bet as a critical factor for IBD. We report here that T-bet deficient mice had a greater cellularity of NKp46-negative ILC3 correlating with enhanced expression of RORγt and IL-7R, but independent of signaling through STAT1 or STAT4. We observed enhanced neutrophilia in the colonic lamina propria (cLP) of these animals, however, we did not detect a greater risk of T-bet-deficient mice to develop spontaneous colitis. Furthermore, by utilizing an in vivo fate-mapping approach, we identified a population of T-bet-positive precursors in NKp46-negative ILC3s. These data suggest that T-bet controls ILC3 cellularity, but does do not drive a pathogenic role of ILC3 in mice with a conventional specific pathogen-free microbiota.

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IL-1β mediates chronic intestinal inflammation by promoting the accumulation of IL-17A secreting innate lymphoid cells and CD4+ Th17 cells

Journal of Experimental Medicine ◽

10.1084/jem.20111453 ◽

2012 ◽

Vol 209 (9) ◽

pp. 1595-1609 ◽

Cited By ~ 308

Author(s):

Margherita Coccia ◽

Oliver J. Harrison ◽

Chris Schiering ◽

Mark J. Asquith ◽

Burkhard Becher ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cd4 T Cells ◽

Intestinal Inflammation ◽

Inflammatory Responses ◽

Innate Lymphoid Cells ◽

Lymphoid Cells ◽

Intestinal Pathology ◽

Bowel Diseases ◽

Chronic Intestinal Inflammation

Although very high levels of interleukin (IL)-1β are present in the intestines of patients suffering from inflammatory bowel diseases (IBD), little is known about the contribution of IL-1β to intestinal pathology. Here, we used two complementary models of chronic intestinal inflammation to address the role of IL-1β in driving innate and adaptive pathology in the intestine. We show that IL-1β promotes innate immune pathology in Helicobacter hepaticus–triggered intestinal inflammation by augmenting the recruitment of granulocytes and the accumulation and activation of innate lymphoid cells (ILCs). Using a T cell transfer colitis model, we demonstrate a key role for T cell–specific IL-1 receptor (IL-1R) signals in the accumulation and survival of pathogenic CD4+ T cells in the colon. Furthermore, we show that IL-1β promotes Th17 responses from CD4+ T cells and ILCs in the intestine, and we describe synergistic interactions between IL-1β and IL-23 signals that sustain innate and adaptive inflammatory responses in the gut. These data identify multiple mechanisms through which IL-1β promotes intestinal pathology and suggest that targeting IL-1β may represent a useful therapeutic approach in IBD.

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TICAM-1/TRIF associates with Act1 and suppresses IL-17 receptor–mediated inflammatory responses

Life Science Alliance ◽

10.26508/lsa.202101181 ◽

2021 ◽

Vol 5 (2) ◽

pp. e202101181

Author(s):

Yusuke Miyashita ◽

Takahisa Kouwaki ◽

Hirotake Tsukamoto ◽

Masaaki Okamoto ◽

Kimitoshi Nakamura ◽

...

Keyword(s):

Map Kinases ◽

Inflammatory Responses ◽

Lymphoid Cells ◽

Negative Regulator ◽

Delayed Type Hypersensitivity ◽

Autoimmune Encephalomyelitis ◽

Cytokines And Chemokines ◽

Enhanced Expression ◽

Tlr3 Signaling

TICAM-1 (also called TRIF) is the sole adaptor of TLR3 that recognizes double-stranded RNA. Here, we report that TICAM-1 is involved not only in TLR3 signaling but also in the cytokine receptor IL-17RA signaling. We found that TICAM-1 bound to IL-17R adaptor Act1 to inhibit the interaction between IL-17RA and Act1. Interestingly, TICAM-1 knockout promoted IL-17RA/Act1 interaction and increased IL-17A–mediated activation of NF-κB and MAP kinases, leading to enhanced expression of inflammatory cytokines and chemokines upon IL-17A stimulation. Moreover, Ticam-1 knockout augmented IL-17A–mediated CXCL1 and CXCL2 expression in vivo, resulting in accumulation of myeloid cells. Furthermore, Ticam-1 knockout enhanced delayed type hypersensitivity and exacerbated experimental autoimmune encephalomyelitis. Ticam-1 knockout promoted accumulation of myeloid and lymphoid cells in the spinal cord of EAE-induced mice. Collectively, these data indicate that TICAM-1 inhibits the interaction between IL-17RA and Act1 and functions as a negative regulator in IL-17A–mediated inflammatory responses.

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Group 2 Innate Lymphoid Cells: A Double-Edged Sword in Cancer?

Cancers ◽

10.3390/cancers12113452 ◽

2020 ◽

Vol 12 (11) ◽

pp. 3452

Author(s):

Enrico Maggi ◽

Irene Veneziani ◽

Lorenzo Moretta ◽

Lorenzo Cosmi ◽

Francesco Annunziato

Keyword(s):

Immune Response ◽

Inflammatory Responses ◽

Cell Subset ◽

Innate Lymphoid Cells ◽

Lymphoid Cells ◽

Th2 Cell ◽

Type 2 Immune Response ◽

Group 2 ◽

Lymphoid Organogenesis

Group 2 Innate Lymphoid Cells (ILC2s) belong to the family of helper ILCs which provide host defense against infectious agents, participate in inflammatory responses and mediate lymphoid organogenesis and tissue repair, mainly at the skin and mucosal level. Based on their transcriptional, phenotypic and functional profile, ILC2s mirror the features of the adaptive CD4+ Th2 cell subset, both contributing to the so-called type 2 immune response. Similar to other ILCs, ILC2s are rapidly activated by signals deriving from tissue and/or other tissue-resident immune cells. The biologic activity of ILCs needs to be tightly regulated in order to prevent them from contributing to severe inflammation and damage in several organs. Indeed, ILC2s display both enhancing and regulatory roles in several pathophysiological conditions, including tumors. In this review, we summarize the actual knowledge about ILC2s ability to induce or impair a protective immune response, their pro- or antitumor activity in murine models, human (children and adults) pathologies and the potential strategies to improve cancer immunotherapy by exploiting the features of ILC2s.

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HMGB1 exacerbates experimental mouse colitis by enhancing innate lymphoid cells 3 inflammatory responses via promoted IL-23 production

Innate Immunity ◽

10.1177/1753425916669862 ◽

2016 ◽

Vol 22 (8) ◽

pp. 696-705 ◽

Cited By ~ 14

Author(s):

Xiangyu Chen ◽

Lingyun Li ◽

Muhammad Noman Khan ◽

Lifeng Shi ◽

Zhongyan Wang ◽

...

Keyword(s):

Intestinal Inflammation ◽

Inflammatory Responses ◽

High Mobility ◽

Innate Lymphoid Cells ◽

Vital Role ◽

Lymphoid Cells ◽

Effector Cells ◽

Bowel Diseases ◽

Underlying Mechanisms ◽

Innate Effector

In inflammatory bowel diseases (IBD), high mobility group box 1 (HMGB1), as an endogenous inflammatory molecule, can promote inflammatory cytokines secretion by acting on TLR2/4 resulting in tissue damage. The underlying mechanisms remain unclear. Here we report a novel role of HMGB1 in controlling the maintenance and function of intestine-resident group-3 innate lymphoid cells (ILC3s) that are important innate effector cells implicated in mucosal homeostasis and IBD pathogenesis. We showed that mice treated with anti-HMGB1 Ab, or genetically deficient for TLR2–/– or TLR4–/– mice, displayed reduced intestinal inflammation. In these mice, the numbers of colonic ILC3s were significantly reduced, and the levels of IL-17 and IL-22 that can be secreted by ILC3s were also decreased in the colon tissues. Furthermore, HMGB1 promoted DCs via TLR2/4 signaling to produce IL-23, activating ILC3s to produce IL-17 and IL-22. Our data thus indicated that the HMGB1-TLR2/4-DCs-IL-23 cascade pathway enhances the functions of ILC3s to produce IL-17 and IL-22, and this signal way might play a vital role in the development of IBD.

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