Inflammatory adaptation in barrier tissues

Interferon lambdas (IFNλ) (also known as type III IFNs) are critical cytokines that combat infection predominantly at barrier tissues, such as the lung, liver and gastrointestinal tract. Humans have four IFNλs (1-4) where IFNλ1-3 show ~80-95% homology and IFNλ4 is the most divergent displaying only ~30% sequence identity. Variants in IFNλ4 in humans are associated with the outcome of infection, such as with hepatitis C virus. However, how IFNλ4 variants impact cytokine signalling in other tissues and how well this is conserved is largely unknown. In this study we address whether differences in antiviral signalling exist between IFNλ4 variants in human hepatocyte and intestinal cells, comparing them to IFNλ3. We demonstrate that compared to IFNλ3, wild-type human IFNλ4 induces a signalling response with distinct magnitudes and kinetics, which is modified by naturally-occurring variants P70S and K154E in both cell types. IFNλ4s distinct antiviral response was more rapid yet transient compared to IFNλ1 and 3. Additionally, divergent antiviral kinetics were also observed using non-human primate IFNλs and cell lines. Furthermore, an IFNλ4-like receptor-interacting interface failed to alter IFNλ1s kinetics. Together our data provide further evidence that major functional differences exist within the IFNλ gene family. These results highlight the possible tissue specialisation of IFNλs and encourage further investigation of the divergent, non-redundant activities of IFNλ4 and other IFNλs.

Download Full-text

Targeting interleukin-17 in chronic inflammatory disease: A clinical perspective

Journal of Experimental Medicine ◽

10.1084/jem.20191123 ◽

2019 ◽

Vol 217 (1) ◽

Cited By ~ 11

Author(s):

Pascale Zwicky ◽

Susanne Unger ◽

Burkhard Becher

Keyword(s):

Rheumatoid Arthritis ◽

Inflammatory Diseases ◽

Chronic Inflammatory Disease ◽

Interleukin 17 ◽

Clinical Perspective ◽

Preclinical Models ◽

Chronic Inflammatory Diseases ◽

Recent Developments ◽

Disease Entities ◽

Barrier Tissues

Chronic inflammatory diseases like psoriasis, Crohn’s disease (CD), multiple sclerosis (MS), rheumatoid arthritis (RA), and others are increasingly recognized as disease entities, where dysregulated cytokines contribute substantially to tissue-specific inflammation. A dysregulation in the IL-23/IL-17 axis can lead to inflammation of barrier tissues, whereas its role in internal organ inflammation remains less clear. Here we discuss the most recent developments in targeting IL-17 for the treatment of chronic inflammation in preclinical models and in patients afflicted with chronic inflammatory diseases.

Download Full-text

How Ah Receptor Ligand Specificity Became Important in Understanding Its Physiological Function

International Journal of Molecular Sciences ◽

10.3390/ijms21249614 ◽

2020 ◽

Vol 21 (24) ◽

pp. 9614

Author(s):

Iain A. Murray ◽

Gary H. Perdew

Keyword(s):

Physiological Function ◽

Innate Immune ◽

Ah Receptor ◽

Ligand Specificity ◽

Aryl Hydrocarbon ◽

Innate Immune Signaling ◽

Tryptophan Metabolites ◽

Barrier Tissues ◽

Endogenous Metabolites

Increasingly, the aryl hydrocarbon receptor (AHR) is being recognized as a sensor for endogenous and pseudo-endogenous metabolites, and in particular microbiota and host generated tryptophan metabolites. One proposed explanation for this is the role of the AHR in innate immune signaling within barrier tissues in response to the presence of microorganisms. A number of cytokine/chemokine genes exhibit a combinatorial increase in transcription upon toll-like receptors and AHR activation, supporting this concept. The AHR also plays a role in the enhanced differentiation of intestinal and dermal epithelium leading to improved barrier function. Importantly, from an evolutionary perspective many of these tryptophan metabolites exhibit greater activation potential for the human AHR when compared to the rodent AHR. These observations underscore the importance of the AHR in barrier tissues and may lead to pharmacologic therapeutic intervention.

Download Full-text

Effect of Tryptophan-Derived AhR Ligands, Kynurenine, Kynurenic Acid and FICZ, on Proliferation, Cell Cycle Regulation and Cell Death of Melanoma Cells—In Vitro Studies

International Journal of Molecular Sciences ◽

10.3390/ijms21217946 ◽

2020 ◽

Vol 21 (21) ◽

pp. 7946

Author(s):

Katarzyna Walczak ◽

Ewa Langner ◽

Anna Makuch-Kocka ◽

Monika Szelest ◽

Karolina Szalast ◽

...

Keyword(s):

Cell Death ◽

Protein Level ◽

Kynurenic Acid ◽

Melanoma Cells ◽

Aryl Hydrocarbon ◽

Tryptophan Metabolites ◽

Rb Phosphorylation ◽

Retinoblastoma Tumor ◽

Barrier Tissues

Tryptophan metabolites: kynurenine (KYN), kynurenic acid (KYNA) and 6-formylindolo[3,2-b]carbazole (FICZ) are considered aryl hydrocarbon receptor (AhR) ligands. AhR is mainly expressed in barrier tissues, including skin, and is involved in various physiological and pathological processes in skin. We studied the effect of KYN, KYNA and FICZ on melanocyte and melanoma A375 and RPMI7951 cell toxicity, proliferation and cell death. KYN and FICZ inhibited DNA synthesis in both melanoma cell lines, but RPMI7951 cells were more resistant to pharmacological treatment. Tested compounds were toxic to melanoma cells but not to normal human adult melanocytes. Changes in the protein level of cyclin D1, CDK4 and retinoblastoma tumor suppressor protein (Rb) phosphorylation revealed different mechanisms of action of individual AhR ligands. Importantly, all tryptophan metabolites induced necrosis, but only KYNA and FICZ promoted apoptosis in melanoma A375 cells. This effect was not observed in RPMI7951 cells. KYN, KYNA and FICZ in higher concentrations inhibited the protein level of AhR but did not affect the gene expression. To conclude, despite belonging to the group of AhR ligands, KYN, KYNA and FICZ exerted different effects on proliferation, toxicity and induction of cell death in melanoma cells in vitro.

Download Full-text

IL33/ST2 Axis in Diabetic Kidney Disease: A Literature Review

Medicina ◽

10.3390/medicina55020050 ◽

2019 ◽

Vol 55 (2) ◽

pp. 50 ◽

Cited By ~ 3

Author(s):

Alessandro Tonacci ◽

Paolina Quattrocchi ◽

Sebastiano Gangemi

Keyword(s):

Kidney Disease ◽

Literature Review ◽

Diabetic Kidney Disease ◽

Inflammatory Diseases ◽

Th2 Cells ◽

Renal Diseases ◽

Diabetic Kidney ◽

Interleukin 33 ◽

Endothelial Barriers ◽

Barrier Tissues

Interleukin-33 (IL-33) is a cytokine belonging to the IL-1 family, playing a role in inflammatory, infectious and autoimmune diseases and expressed in the cellular nucleus in several tissues. High levels of IL-33 are expressed in epithelial barrier tissues and endothelial barriers. ST2 is a receptor for IL-33, expressed selectively on a subset of Th2 cells, mediating some of their functions. The IL-33/ST2 axis plays an important role in several acute and chronic inflammatory diseases, including asthma and rheumatoid arthritis. Different disorders are related to the activity of IL-33, ST2, or their axis, including cardiovascular disease or renal disturbances. Therefore, in the present work, a literature review was conducted, covering the period from 1 January 2000 to 30 November 2018, in PubMed, ScienceDirect, and Google Scholar database, to assess the involvement of the IL-33/ST2 axis in diabetic kidney disease. 6 articles directly dealing with the argument were identified, highlighting a clear link between IL-33/ST2 axis and diabetic kidney disease or related nephropathy. Overall, the involvement of ST2 seems to be more predictive than IL-33, especially in investigating the deterioration of kidney function; however, both compounds are pivotal in the field of renal diseases. Future studies are required to confirm the scientific evidences on larger and more heterogeneous cohorts.

Download Full-text

Circulating immunity protects the female reproductive tract from Chlamydia infection

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2104407118 ◽

2021 ◽

Vol 118 (21) ◽

pp. e2104407118

Author(s):

Jasmine C. Labuda ◽

Oanh H. Pham ◽

Claire E. Depew ◽

Kevin D. Fong ◽

Bokyung S. Lee ◽

...

Keyword(s):

T Cells ◽

Cd4 T Cells ◽

Reproductive Tract ◽

Vaccine Development ◽

Female Reproductive Tract ◽

Chlamydia Infection ◽

Immune Memory ◽

Memory Cd4 T Cells ◽

Barrier Tissues ◽

Memory Lymphocytes

Anatomical positioning of memory lymphocytes within barrier tissues accelerates secondary immune responses and is thought to be essential for protection at mucosal surfaces. However, it remains unclear whether resident memory in the female reproductive tract (FRT) is required for Chlamydial immunity. Here, we describe efficient generation of tissue-resident memory CD4 T cells and memory lymphocyte clusters within the FRT after vaginal infection with Chlamydia. Despite robust establishment of localized memory lymphocytes within the FRT, naïve mice surgically joined to immune mice, or mice with only circulating immunity following intranasal immunization, were fully capable of resisting Chlamydia infection via the vaginal route. Blocking the rapid mobilization of circulating memory CD4 T cells to the FRT inhibited this protective response. These data demonstrate that secondary protection in the FRT can occur in the complete absence of tissue-resident immune cells. The ability to confer robust protection to barrier tissues via circulating immune memory provides an unexpected opportunity for vaccine development against infections of the FRT.

Download Full-text

Systemic inflammation suppresses lymphoid tissue remodeling and B cell immunity during concomitant local infection

10.1101/831081 ◽

2019 ◽

Author(s):

Yannick O Alexandre ◽

Sapna Devi ◽

Simone L Park ◽

Laura K. Mackay ◽

William R. Heath ◽

...

Keyword(s):

B Cell ◽

Systemic Inflammation ◽

Systemic Infection ◽

Type I ◽

Local Immunity ◽

Cell Immunity ◽

Draining Lymph Node ◽

Regional Immunity ◽

Barrier Tissues ◽

The Impact

AbstractConcurrent infection with multiple pathogens occurs frequently in individuals and can result in exacerbated infections and altered immunity. However, the impact of such coinfections on immune responses remains poorly understood. Here we reveal that systemic infection results in an inflammation-induced suppression of local immunity. During localized infection or vaccination in barrier tissues including the skin or respiratory tract, concurrent systemic infection induced a type I interferon-dependent lymphopenia that impairs lymphocyte recruitment to the draining lymph node (dLN). This leads to suppressed lymphoid stromal cell expansion and dLN remodeling and impaired induction of B cell responses and antibody production. Our data suggest that contemporaneous systemic inflammation constrains the induction of regional immunity.

Download Full-text

Macrophage-Mediated Tissue Vascularization: Similarities and Differences Between Cornea and Skin

Frontiers in Immunology ◽

10.3389/fimmu.2021.667830 ◽

2021 ◽

Vol 12 ◽

Author(s):

Karina Hadrian ◽

Sebastian Willenborg ◽

Felix Bock ◽

Claus Cursiefen ◽

Sabine A. Eming ◽

...

Keyword(s):

Lymphatic Vessel ◽

Molecular Mechanisms ◽

Inflammatory Responses ◽

Tissue Injury ◽

Corneal Transplantation ◽

Vascular Growth ◽

Corneal Wound ◽

Vessel Growth ◽

Health And Disease ◽

Barrier Tissues

Macrophages are critical mediators of tissue vascularization both in health and disease. In multiple tissues, macrophages have been identified as important regulators of both blood and lymphatic vessel growth, specifically following tissue injury and in pathological inflammatory responses. In development, macrophages have also been implicated in limiting vascular growth. Hence, macrophages provide an important therapeutic target to modulate tissue vascularization in the clinic. However, the molecular mechanisms how macrophages mediate tissue vascularization are still not entirely resolved. Furthermore, mechanisms might also vary among different tissues. Here we review the role of macrophages in tissue vascularization with a focus on their role in blood and lymphatic vessel formation in the barrier tissues cornea and skin. Comparing mechanisms of macrophage-mediated hem- and lymphangiogenesis in the angiogenically privileged cornea and the physiologically vascularized skin provides an opportunity to highlight similarities but also tissue-specific differences, and to understand how macrophage-mediated hem- and lymphangiogenesis can be exploited for the treatment of disease, including corneal wound healing after injury, graft rejection after corneal transplantation or pathological vascularization of the skin.

Download Full-text

Developing human fetal skin demonstrates a unique lymphocyte signature

10.1101/2020.06.16.153593 ◽

2020 ◽

Author(s):

Miqdad O. Dhariwala ◽

Dhuvarakesh Karthikeyan ◽

Kimberly S. Vasquez ◽

Sepideh Farhat ◽

Keyon Taravati ◽

...

Keyword(s):

Effector Memory ◽

Follicle Development ◽

Second Trimester ◽

Fetal Skin ◽

Regional Association ◽

Skin Immunity ◽

Hair Follicle Development ◽

Barrier Tissues ◽

Early Features ◽

Developmental Windows

SummaryLymphocytes in barrier tissues play critical roles in host defense and homeostasis. These cells take up residence in tissues during defined developmental windows, when they may demonstrate distinct phenotypes and functions. Here, we utilized mass and flow cytometry to elucidate early features of human skin immunity, demonstrating a unique fetal skin lymphocyte signature. While most conventional αβ T (Tconv) cells in fetal skin have a naïve, proliferative phenotype, a subset of CD4+ Tconv and CD8+ cells demonstrate memory-like features and a propensity for IFNγ production. Skin regulatory T cells dynamically accumulate over the second trimester in temporal and regional association with hair follicle development. These fetal skin Tregs demonstrate an effector memory phenotype while differing from their adult counterparts in expression of key effector molecules. Thus, we identify features of prenatal skin lymphocytes that may have key implications for understanding antigen and allergen encounters in utero and in infancy.

Download Full-text