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

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.

Download Full-text

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.

Download Full-text

Oral Supplementation With Selected Lactobacillus Acidophilus Triggers Antimicrobial Response, Activation of Innate Lymphoid Cells Type 3 And Improves Colitis

10.21203/rs.3.rs-731878/v1 ◽

2021 ◽

Author(s):

Jiří Hrdý ◽

Aurélie Couturier-Maillard ◽

Denise Boutillier ◽

Carmen Lapadatescu ◽

Philippe Blanc ◽

...

Keyword(s):

Inflammatory Bowel Diseases ◽

Lactobacillus Acidophilus ◽

Target Genes ◽

Intestinal Inflammation ◽

Probiotic Strain ◽

Innate Lymphoid Cells ◽

Lymphoid Cells ◽

Trinitrobenzene Sulfonic Acid ◽

Bowel Diseases ◽

Inflammatory Bowel

Abstract Live biotherapeutic products constitute an emerging therapeutic approach to prevent or treat inflammatory bowel diseases. Lactobacillus acidophilus is a constituent of the human microbiota with probiotic potential, that are illustrated by direct and indirect antimicrobial activity against several pathogens and improvement of intestinal inflammation. In this study, we evaluated the anti-inflammatory properties of the L. acidophilus strain BIO5768 and assessed the underlying mechanisms of action. BIO5768 was able to counteract the acute colitis that is induced by 2,4,6-trinitrobenzene sulfonic acid (TNBS). When administered alone or in combination with Bifidobacterium animalis spp. lactis BIO5764 and Limosilactobacillus reuteri, BIO5768 was also able to alleviate intestinal inflammation induced by Citrobacter rodentium infection. Supplementation of naïve mice with either strain BIO5768 alone or as mixture, increased the gene expression of several target genes involved in immune signaling, including c-type lectin Reg3 gamma. Consistently, the ability of innate lymphoid cells to secrete IL-22 was enhanced in response to BIO5768. Interestingly, the aforementioned responses were shown to be independent of NOD2 and Th17 signaling in mice that were mono-colonized with BIO5768. In conclusion, we identify a new potential probiotic strain with the ability for the management of inflammatory bowel diseases, and provide some insights into its mode of action.

Download Full-text

IL-12 drives functional plasticity of human group 2 innate lymphoid cells

Journal of Experimental Medicine ◽

10.1084/jem.20151750 ◽

2016 ◽

Vol 213 (4) ◽

pp. 569-583 ◽

Cited By ~ 144

Author(s):

Ai Ing Lim ◽

Silvia Menegatti ◽

Jacinta Bustamante ◽

Lionel Le Bourhis ◽

Matthieu Allez ◽

...

Keyword(s):

Ex Vivo ◽

Human Peripheral Blood ◽

Innate Lymphoid Cells ◽

Lymphoid Cells ◽

Functional Plasticity ◽

Effector Cells ◽

Ifn Γ ◽

Group 2 ◽

Innate Effector

Group 2 innate lymphoid cells (ILC2) include IL-5– and IL-13–producing CRTh2+CD127+ cells that are implicated in early protective immunity at mucosal surfaces. Whereas functional plasticity has been demonstrated for both human and mouse ILC3 subsets that can reversibly give rise to IFN-γ–producing ILC1, plasticity of human or mouse ILC2 has not been shown. Here, we analyze the phenotypic and functional heterogeneity of human peripheral blood ILC2. Although subsets of human CRTh2+ ILC2 differentially express CD117 (c-kit receptor), some ILC2 surface phenotypes are unstable and can be modulated in vitro. Surprisingly, human IL-13+ ILC2 can acquire the capacity to produce IFN-γ, thereby generating plastic ILC2. ILC2 cultures demonstrated that IFN-γ+ ILC2 clones could be derived and were stably associated with increased T-BET expression. The inductive mechanism for ILC2 plasticity was mapped to the IL-12–IL-12R signaling pathway and was confirmed through analysis of patients with Mendelian susceptibility to mycobacterial disease due to IL-12Rβ1 deficiencies that failed to generate plastic ILC2. We also detected IL-13+IFN-γ+ ILC2 ex vivo in intestinal samples from Crohn’s disease patients. These results demonstrate cytokine production plasticity for human ILC2 and further suggest that environmental cues can dictate ILC phenotype and function for these tissue-resident innate effector cells.

Download Full-text

ILC3 GM-CSF production and mobilisation orchestrate acute intestinal inflammation

eLife ◽

10.7554/elife.10066 ◽

2016 ◽

Vol 5 ◽

Cited By ~ 96

Author(s):

Claire Pearson ◽

Emily E Thornton ◽

Brent McKenzie ◽

Anna-Lena Schaupp ◽

Nicky Huskens ◽

...

Keyword(s):

Intestinal Inflammation ◽

Temporal Dynamics ◽

Control Point ◽

Small Population ◽

Lymphoid Cells ◽

Effector Cells ◽

Gm Csf ◽

Inflammatory Monocytes ◽

Spatio Temporal ◽

Innate Effector

Innate lymphoid cells (ILCs) contribute to host defence and tissue repair but can induce immunopathology. Recent work has revealed tissue-specific roles for ILCs; however, the question of how a small population has large effects on immune homeostasis remains unclear. We identify two mechanisms that ILC3s utilise to exert their effects within intestinal tissue. ILC-driven colitis depends on production of granulocyte macrophage-colony stimulating factor (GM-CSF), which recruits and maintains intestinal inflammatory monocytes. ILCs present in the intestine also enter and exit cryptopatches in a highly dynamic process. During colitis, ILC3s mobilize from cryptopatches, a process that can be inhibited by blocking GM-CSF, and mobilization precedes inflammatory foci elsewhere in the tissue. Together these data identify the IL-23R/GM-CSF axis within ILC3 as a key control point in the accumulation of innate effector cells in the intestine and in the spatio-temporal dynamics of ILCs in the intestinal inflammatory response.

Download Full-text

Faculty Opinions recommendation of Interleukin-15-dependent NKp46+ innate lymphoid cells control intestinal inflammation by recruiting inflammatory monocytes.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.717951515.793456819 ◽

2012 ◽

Author(s):

Xian C Li

Keyword(s):

Intestinal Inflammation ◽

Innate Lymphoid Cells ◽

Lymphoid Cells ◽

Inflammatory Monocytes ◽

Interleukin 15

Download Full-text

Innate Lymphoid Cells in Intestinal Inflammation

Frontiers in Immunology ◽

10.3389/fimmu.2017.01296 ◽

2017 ◽

Vol 8 ◽

Cited By ~ 55

Author(s):

Alessandra Geremia ◽

Carolina V. Arancibia-Cárcamo

Keyword(s):

Intestinal Inflammation ◽

Innate Lymphoid Cells ◽

Lymphoid Cells

Download Full-text

STAT3 Genotypic Variant rs744166 and Increased Tyrosine Phosphorylation of STAT3 in IL-23 Responsive Innate Lymphoid Cells during Pathogenesis of Crohn’s Disease

Journal of Immunology Research ◽

10.1155/2019/9406146 ◽

2019 ◽

Vol 2019 ◽

pp. 1-10 ◽

Cited By ~ 1

Author(s):

Ying Tang ◽

Sanda A. Tan ◽

Atif Iqbal ◽

Jian Li ◽

Sarah C. Glover

Keyword(s):

Crohn’S Disease ◽

Crohn's Disease ◽

Immune Responses ◽

Tyrosine Phosphorylation ◽

Innate Lymphoid Cells ◽

Immune Defense ◽

Lymphoid Cells ◽

Dependent Manner ◽

Regulatory Pathways ◽

Innate Effector

Crohn’s disease (CD) results from dysregulated immune responses to gut microbiota in genetically susceptible individuals, affecting multiple areas of the gastrointestinal tract. Innate lymphoid cells (ILCs) are tissue-resident innate effector lymphocytes which play crucial roles in mucosal immune defense, tissue repair, and maintenance of homeostasis. The accumulation of IFN-γ-producing ILC1s and increased level of proinflammatory cytokines produced by ILCs has been observed in the inflamed terminal ileum of CD patients. To date, the precise mechanisms of ILC plasticity and gene regulatory pathways in ILCs remain unclear. Signal transducer and activator of transcription 3 (STAT3) regulates gene expression in a cell-specific, cytokine-dependent manner, involving multiple immune responses. This study proposes the positive correlation between the prevalence of STAT3 rs744166 risky allele “A” with the severity of disease in a cohort of 94 CD patients. In addition, the results suggest an increased STAT3 activity in the inflamed ileum of CD patients, compared to unaffected ileum sections. Notably, IL-23 triggers the differentiation of CD117+NKp44- ILC3s and induces the activation of STAT3 in both CD117+NKp44- and CD117-NKp44- ILC subsets, implying the involvement of STAT3 in the initiation of ILC plasticity. Moreover, carriage of STAT3 “A” risk allele exhibited a higher basal level of STAT3 tyrosine phosphorylation, and an increased IL-23 triggered the pSTAT3 level. We also demonstrated that there was no delayed dephosphorylation of STAT3 in ILCs of both A/A and G/G donors. Overall, the results of this study suggest that IL-23-induced activation of STAT3 in the CD117-NKp44- ILC1s involves in ILC1-to-ILC3 plasticity and a potential regulatory role of ILC1 function. Those genetically susceptible individuals carried STAT3 rs744166 risky allele appear to have higher basal and cytokine-stimulated activation of STAT3 signal, leading to prolonged inflammation and chronic relapse.

Download Full-text

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.

Download Full-text