New perspectives on IL-33 and IL-1 family cytokines as innate environmental sensors

2018 ◽  
Vol 46 (5) ◽  
pp. 1345-1353 ◽  
Author(s):  
Ian C. Scott ◽  
D. Gareth Rees ◽  
E. Suzanne Cohen
Keyword(s):  
Immune Responses ◽  
Allergic Inflammation ◽  
Proteolytic Processing ◽  
Innate Immune ◽  
Environmental Sensors ◽  
Biological Functions ◽  
Soluble Receptors ◽  
Direct Sensing ◽  
Proteolytic Activities

Interleukin (IL)-1 family cytokines are important initiators of innate immunity and host defence; however, their uncontrolled activities can cause tissue-damaging inflammation. Consequently, IL-1 family cytokines have sophisticated regulatory mechanisms to control their activities including proteolytic processing for their activation and the deployment of soluble receptors and receptor antagonists to limit their activities. IL-33 is a promoter of type 2 immunity and allergic inflammation through its alarmin activity that can rapidly initiate local immune responses by stimulating innate immune cells following exposure to environmental insults, pathogens, or sterile injury. Recent publications have provided new insights into how the range and duration of IL-33 activity is regulated by direct sensing of host-derived and exogenous proteolytic activities as well as oxidative changes during tissue damage. Here, we discuss how this impacts our understanding of the roles of IL-33 in initiating immune responses and the evidence that these sensing mechanisms might regulate the activities of other IL-1 family cytokines and their biological functions. Finally, we discuss translational challenges these discoveries pose for the accurate detection of different forms of these cytokines.

Interferon and IL-27 antagonize the function of group 2 innate lymphoid cells and type 2 innate immune responses

2015 ◽  
Vol 17 (1) ◽  
pp. 76-86 ◽  
Author(s):  
Kazuyo Moro ◽  
Hiroki Kabata ◽  
Masanobu Tanabe ◽  
Satoshi Koga ◽  
Natsuki Takeno ◽  
...  
Keyword(s):  
Immune Responses ◽  
Innate Lymphoid Cells ◽  
Innate Immune ◽  
Lymphoid Cells ◽  
Innate Immune Responses ◽  
Group 2

scholarly journals Serum proteomics reveals systemic dysregulation of innate immunity in type 1 diabetes

2012 ◽  
Vol 210 (1) ◽  
pp. 191-203 ◽  
Author(s):  
Qibin Zhang ◽  
Thomas L. Fillmore ◽  
Athena A. Schepmoes ◽  
Therese R.W. Clauss ◽  
Marina A. Gritsenko ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Immune Responses ◽  
Innate Immune ◽  
Healthy Controls ◽  
Innate Immune Responses ◽  
C1 Inhibitor ◽  
Serum Samples ◽  
Healthy Control

Using global liquid chromatography-mass spectrometry (LC-MS)–based proteomics analyses, we identified 24 serum proteins that were significantly variant between those with type 1 diabetes (T1D) and healthy controls. Functionally, these proteins represent innate immune responses, the activation cascade of complement, inflammatory responses, and blood coagulation. Targeted verification analyses were performed on 52 surrogate peptides representing these proteins, with serum samples from an antibody standardization program cohort of 100 healthy control and 50 type 1 diabetic subjects. 16 peptides were verified as having very good discriminating power, with areas under the receiver operating characteristic curve ≥0.8. Further validation with blinded serum samples from an independent cohort (10 healthy control and 10 type 1 diabetics) demonstrated that peptides from platelet basic protein and C1 inhibitor achieved both 100% sensitivity and 100% specificity for classification of samples. The disease specificity of these proteins was assessed using sera from 50 age-matched type 2 diabetic individuals, and a subset of proteins, C1 inhibitor in particular, were exceptionally good discriminators between these two forms of diabetes. The panel of biomarkers distinguishing those with T1D from healthy controls and those with type 2 diabetes suggests that dysregulated innate immune responses may be associated with the development of this disorder.

scholarly journals Spatial and temporal regulation of cytokine expression in Type 2 immune responses

2021 ◽  
Author(s):  
◽  
Ryan Kyle
Keyword(s):  
T Cells ◽  
Lymph Node ◽  
Immune Responses ◽  
Cd4 T Cells ◽  
Helminth Infection ◽  
Allergic Inflammation ◽  
Nippostrongylus Brasiliensis ◽  
Reporter Mice

<p>Type 2 immune responses are generated to provide protection against parasitic helminth infections, however these responses also cause the pathologies associated with allergic inflammation. Studies of the cell types and signalling pathways that mediate Type 2 immune responses have been previously undertaken with the goals of efficient development of vaccines against helminths, and identification of pathways that can be inhibited to decrease the damage caused by allergic inflammation.  The cytokines interleukin-4 (IL-4) and interleukin-13 (IL-13) mediate many of the downstream effector functions of the Type 2 immune response. To study the mechanisms that control expression of these two cytokines I have used a novel dual cytokine IL-4 and IL-13 transgenic reporter mouse. Utilising this tool along with other IL-4 reporter mice I have discovered that the amount of T cell receptor (TCR) signalling modulates the allelic expression of IL-4 by CD4⁺ T cells. The transgenic IL-4 reporter mouse has for the first time allowed independent measurement of the effects of IL-4 deficiency on the expression of IL-4 in vivo. Using this system I have found that IL- 4 is not required for the in vivo generation or expansion of IL-4 producing CD4⁺ T cells. Th2 differentiated CD4⁺ T cells also expresses IL-13, however the dual reporter mice have demonstrated that IL-13 is expressed consistently later than IL-4 in vitro, and IL-13 requires constant, or multiple exposures to TCR stimulus for expression to be induced. IL-13 expression is absent from lymph node CD4⁺ T cells during exposure to allergens or helminth infection. Sequestration of CD4⁺ T cells in the lymph node does not impact the number of IL-13 expressing CD4⁺ T cells in the lung during a helminth infection, indicating that adaptive immune cell derived IL-13 may be entirely produced by lung resident cells not requiring transit through the lymph node.  I have characterised a population of innate lymphoid cells (ILCs) within the skin and found that the proportion of these cells that constitutively express IL-13 decreases with age. These cells did not drastically change in numbers or IL-13 responses in a range of inflammatory conditions including a model of atopic dermatitis. Basophils were found to respond to the atopic dermatitis model by migrating specifically to the treated skin site and draining lymph node, and producing IL-4 in a thymic stromal lymphopoietin dependant manner.  Treatment with exogenous cytokines induced IL-13 expression from group 2 ILCs (ILC2s) in the lung and these cells promoted protective immune responses against Nippostrongylus brasiliensis infection. The immune response generated during a primary infection by Nippostrongylus brasiliensis provides protection from re-infection. Long-term protection is dependent on CD4⁺ T cells but when sufficiently stimulated by cytokine, ILC2s can rescue the protection lost by the depletion of CD4⁺ T cells.  This thesis has shown that CD4⁺ T cells and populations of innate immune cells differentially regulate the expression of the closely related Type 2 cytokines IL-4 and IL- 13. These discoveries will help direct future research aiming to boost the effectiveness of anti-helminth vaccines, or decrease the pathology caused by allergic diseases by targeting specific cytokine expression.</p>

scholarly journals Caspases in Cell Death, Inflammation, and Pyroptosis

2020 ◽  
Vol 38 (1) ◽  
pp. 567-595 ◽  
Author(s):  
Sannula Kesavardhana ◽  
R.K. Subbarao Malireddi ◽  
Thirumala-Devi Kanneganti
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Immune Responses ◽  
Cross Talk ◽  
Cysteine Proteases ◽  
Proteolytic Processing ◽  
Innate Immune ◽  
Innate Immune Responses ◽  
New Research ◽  
Multicellular Organisms

Caspases are a family of conserved cysteine proteases that play key roles in programmed cell death and inflammation. In multicellular organisms, caspases are activated via macromolecular signaling complexes that bring inactive procaspases together and promote their proximity-induced autoactivation and proteolytic processing. Activation of caspases ultimately results in programmed execution of cell death, and the nature of this cell death is determined by the specific caspases involved. Pioneering new research has unraveled distinct roles and cross talk of caspases in the regulation of programmed cell death, inflammation, and innate immune responses. In-depth understanding of these mechanisms is essential to foster the development of precise therapeutic targets to treat autoinflammatory disorders, infectious diseases, and cancer. This review focuses on mechanisms governing caspase activation and programmed cell death with special emphasis on the recent progress in caspase cross talk and caspase-driven gasdermin D–induced pyroptosis.

The chemerin-CMKLR1 axis limits thermogenesis by controlling a beige adipocyte/IL-33/type 2 innate immunity circuit

2021 ◽  
Vol 6 (61) ◽  
pp. eabg9698
Author(s):  
Yuli Lin ◽  
Liuling Xiao ◽  
Qian Cai ◽  
Cuisong Zhu ◽  
Shufen Li ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Immune Responses ◽  
Metabolic Disorders ◽  
Innate Immune ◽  
Negative Regulator ◽  
Innate Immune Responses ◽  
Cold Stimulation ◽  
Beige Adipocytes ◽  
Beige Fat

IL-33–associated type 2 innate immunity has been shown to support beige fat formation and thermogenesis in subcutaneous inguinal white adipose tissue (iWAT), but little is known about how it is regulated in iWAT. Chemerin, as a newly identified adipokine, is clinically associated with obesity and metabolic disorders. We here show that cold exposure specifically reduces chemerin and its receptor chemerin chemokine-like receptor 1 (CMKLR1) expression in iWAT. Lack of chemerin or adipocytic CMKLR1 enhances cold-induced thermogenic beige fat via potentiating type 2 innate immune responses. Mechanistically, we identify adipocytes, particularly beige adipocytes, as the main source for cold-induced IL-33, which is restricted by the chemerin-CMKLR1 axis via dampening cAMP-PKA signaling, thereby interrupting a feed-forward circuit between beige adipocytes and type 2 innate immunity that is required for cold-induced beige fat and thermogenesis. Moreover, specific deletion of adipocytic IL-33 inhibits cold-induced beige fat and type 2 innate immune responses. Last, genetic blockade of adipocytic CMKLR1 protects against diet-induced obesity and enhances the metabolic benefits of cold stimulation in preestablished obese mice. Thus, our study identifies the chemerin-CMKLR1 axis as a physiological negative regulator of thermogenic beige fat via interrupting adipose-immune communication and suggests targeting adipose CMKLR1 as a potential therapeutic strategy for obesity-related metabolic disorders.

scholarly journals Adaptive Immunity and Antigen-Specific Activation in Obesity-Associated Insulin Resistance

2015 ◽  
Vol 2015 ◽  
pp. 1-15 ◽  
Author(s):  
Melissa Hui Yen Chng ◽  
Michael N. Alonso ◽  
Sarah E. Barnes ◽  
Khoa D. Nguyen ◽  
Edgar G. Engleman
Keyword(s):  
Insulin Resistance ◽  
Immune System ◽  
Immune Responses ◽  
Adaptive Immune System ◽  
Innate Immune ◽  
T Cell Subsets ◽  
Adaptive Immune ◽  
Adipose Tissue Depots ◽  
B And T Lymphocytes

Type 2 diabetes mellitus (T2D) is a metabolic disease that is strongly tied to obesity and often preceded by insulin resistance (IR). It has been established that chronic inflammation of hypertrophic adipose tissue depots in obese individuals leads to obesity-associated IR and is mediated by cells of the innate immune system, particularly macrophages. More recently, cells of the adaptive immune system, B and T lymphocytes, have also emerged as important regulators of glucose homeostasis, raising the intriguing possibility that antigen-driven immune responses play a role in disease. In this review, we critically evaluate the roles that various B and T cell subsets play in IR, and then we examine the data suggesting that antigen-driven mechanisms, such as antigen presentation and costimulation, may drive the activity of these lymphocytes.

scholarly journals IL-33, an Alarmin of the IL-1 Family Involved in Allergic and Non Allergic Inflammation: Focus on the Mechanisms of Regulation of Its Activity

Cells ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 107
Author(s):  
Corinne Cayrol
Keyword(s):  
Interleukin 1 ◽  
Allergic Inflammation ◽  
Proteolytic Processing ◽  
Lymphoid Cells ◽  
Target Cells ◽  
Interleukin 33 ◽  
Promising Therapeutic Target ◽  
St2 Receptor ◽  
Barrier Tissues

Interleukin-33 (IL-33) is a member of the interleukin-1 (IL-1) family that is expressed in the nuclei of endothelial and epithelial cells of barrier tissues, among others. It functions as an alarm signal that is released upon tissue or cellular injury. IL-33 plays a central role in the initiation and amplification of type 2 innate immune responses and allergic inflammation by activating various target cells expressing its ST2 receptor, including mast cells and type 2 innate lymphoid cells. Depending on the tissue environment, IL-33 plays a wide variety of roles in parasitic and viral host defense, tissue repair and homeostasis. IL-33 has evolved a variety of sophisticated regulatory mechanisms to control its activity, including nuclear sequestration and proteolytic processing. It is involved in many diseases, including allergic, inflammatory and infectious diseases, and is a promising therapeutic target for the treatment of severe asthma. In this review, I will summarize the literature around this fascinating pleiotropic cytokine. In the first part, I will describe the basics of IL-33, from the discovery of interleukin-33 to its function, including its expression, release and signaling pathway. The second part will be devoted to the regulation of IL-33 protein leading to its activation or inactivation.

scholarly journals Impaired Inflammatory Response to LPS in Type 2 Diabetes Mellitus

2018 ◽  
Vol 2018 ◽  
pp. 1-6 ◽  
Author(s):  
Lusine Khondkaryan ◽  
Sona Margaryan ◽  
David Poghosyan ◽  
Gayane Manukyan
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Immune Responses ◽  
Innate Immune ◽  
Innate Immune Responses ◽  
Lps Challenge ◽  
High Incidence ◽  
Severe Health Problem

Type 2 diabetes mellitus (T2DM) is a severe health problem worldwide, reaching epidemic levels. High susceptibility to infections of T2DM patients indicates dysregulated immune responses to pathogens. However, innate immune responses, including monocyte functions, in T2DM are poorly investigated. Therefore, in this study we aimed to assess lipopolysaccharide- (LPS-) induced immune responses of circulating monocytes from T2DM patients. The results showed that monocytes from T2DM were hyporesponsive to LPS challenge as reflected by significantly suppressed secretion of TNFα (p<0.01) and expression of CD11b (p<0.001) and TLR4 (p<0.001) compared to those in monocytes from healthy subjects. Furthermore, LPS-induced IL-10 levels were similar in diabetic and healthy supernatants, while expression levels of CD163 were found to be downregulated on monocytes from T2DM (p<0.001) suggesting impaired ability of monocytes to switch their phenotype to anti-inflammatory. Taken together, our results suggest compromised function of monocytes in T2DM, which may explain, at least partly, high incidence of infection in these patients.

scholarly journals Detection of succinate by intestinal tuft cells triggers a type 2 innate immune circuit

2018 ◽  
Author(s):  
Marija S. Nadjsombati ◽  
John W. McGinty ◽  
Miranda R. Lyons-Cohen ◽  
Joshua L. Pollack ◽  
G.A. Nagana Gowda ◽  
...  
Keyword(s):  
Small Intestine ◽  
Immune Responses ◽  
Innate Immune ◽  
Nippostrongylus Brasiliensis ◽  
Transduction Pathway ◽  
Type 2 Immunity ◽  
Tuft Cell ◽  
Tuft Cells ◽  
Taste Transduction

SummaryInitiation of immune responses requires innate immune sensing, but immune detection of the helminths, protists, and allergens that stimulate type 2 immunity remains poorly understood. In the small intestine, type 2 immune responses are regulated by a tuft cell-ILC2 signaling circuit. Tuft cells express components of a canonical taste transduction pathway, including the membrane channel TRPM5, but the ligands and receptors that activate tuft cells in the small intestine are unknown. Here we identify succinate as the first ligand that activates intestinal tuft cells to initiate type 2 immune responses. Using mRNA-Seq on tuft cells from different tissues, we show that all tuft cells express the intracellular taste transduction pathway, but expression of upstream receptors is tissue-specific. In the small intestine, tuft cells express the succinate receptor SUCNR1. Remarkably, providing succinate in drinking water is sufficient to induce a multifaceted type 2 immune response in the murine small intestine, involving all known components of the tuft-ILC2 circuit. The helminthNippostrongylus brasiliensissecretes succinate as a metabolite, and sensing of both succinate andN. brasiliensisrequires tuft cells and TRPM5, suggesting a novel paradigm in which type 2 immunity monitors microbial metabolism. Manipulation of succinate sensing may have therapeutic benefit in numerous intestinal diseases.

Sign in / Sign up

Export Citation Format

Share Document