ATG16L1 negatively regulates RICK/RIP2-mediated innate immune responses

Abstract Polymorphisms in the autophagy-related protein 16 like 1 (ATG16L1) and nucleotide-binding oligomerization domain 2 (NOD2) genes are associated with Crohn’s disease (CD). Impaired interaction between ATG16L1 and NOD2 underlies CD immunopathogenesis. Although activation of the receptor-interacting serine–threonine kinase (RICK, also known as RIP2), a downstream signaling molecule for NOD2 and multiple toll-like receptors (TLRs), plays a pathogenic role in the development of inflammatory bowel disease, the molecular interaction between ATG16L1 and RICK/RIP2 remains poorly understood. In this study, we examined the physical interaction between ATG16L1 and RICK/RIP2 in human embryonic kidney 293 cells and human monocyte-derived dendritic cells (DCs) expressing excessive and endogenous levels of these proteins, respectively. We established that ATG16L1 binds to RICK/RIP2 kinase domain and negatively regulates TLR2-mediated nuclear factor-kappa B (NF-κB) activation and pro-inflammatory cytokine responses by inhibiting the interaction between TLR2 and RICK/RIP2. Binding of ATG16L1 to RICK/RIP2 suppressed NF-κB activation by down-regulating RICK/RIP2 polyubiquitination. Notably, the percentage of colonic DCs expressing ATG16L1 inversely correlated with IL-6 and TNF-α expression levels in the colon of CD patients. These data suggest that the interaction between ATG16L1 and RICK/RIP2 maintains intestinal homeostasis via the down-regulation of TLR-mediated pro-inflammatory cytokine responses.

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Candida tropicalis induces pro-inflammatory cytokine production, NF-κB and MAPKs pathways regulation, and dectin-1 activation

Canadian Journal of Microbiology ◽

10.1139/cjm-2017-0559 ◽

2018 ◽

Vol 64 (12) ◽

pp. 937-944 ◽

Cited By ~ 2

Author(s):

Zhimin Duan ◽

Qing Chen ◽

Rong Zeng ◽

Leilei Du ◽

Caixia Liu ◽

...

Keyword(s):

Signaling Pathways ◽

Inflammatory Cytokine ◽

Mononuclear Cells ◽

Human Peripheral Blood ◽

Mapk Signaling ◽

Dependent Manner ◽

Peripheral Blood Mononuclear ◽

Downstream Signaling ◽

Tnf Α ◽

Mitogen Activated Protein

The prevalence of Candida infection induced by non-albicans Candida (NAC) species is increasing. However, as a common NAC species, C. tropicalis has received much less study in terms of host immunity than C. albicans has. In this study, we evaluated the pro-inflammatory cytokine responses evoked by C. tropicalis and determined whether dectin-1 and downstream NF-κB and mitogen-activated protein kinases (MAPKs) signaling pathways played roles in inflammation in human peripheral blood mononuclear cells (PBMCs) and THP-1 macrophage-like cells. Exposure of PBMCs and THP-1 macrophage-like cells to C. tropicalis led to the enhanced gene expression and secretion of TNF-α and IL-6 in a time- and dose-dependent manner. THP-1 macrophage-like cells being challenged by C. tropicalis resulted in the activation of the NF-κB, p38, and ERK1/2 MAPK signaling pathways. We also found that the expression of dectin-1 was increased with C. tropicalis treatment. These data reveal that dectin-1 may play a role in sensing the inflammation response induced by C. tropicalis and that NF-κB and MAPK are involved in the downstream signaling pathways in macrophages.

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Key differences between olfactory ensheathing cells and Schwann cells regarding phagocytosis of necrotic cells: implications for transplantation therapies

Scientific Reports ◽

10.1038/s41598-020-75850-8 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

L. Nazareth ◽

T. B. Shelper ◽

A. Chacko ◽

S. Basu ◽

A. Delbaz ◽

...

Keyword(s):

Nervous System ◽

Schwann Cells ◽

Inflammatory Cytokine ◽

Time Course ◽

Olfactory Ensheathing Cells ◽

Cytokine Responses ◽

Tnf Α ◽

Myelin Debris ◽

Ensheathing Cells ◽

Pro Inflammatory Cytokines

Abstract Transplantation of peripheral nervous system glia is being explored for treating neural injuries, in particular central nervous system injuries. These glia, olfactory ensheathing cells (OECs) and Schwann cells (SCs), are thought to aid regeneration by clearing necrotic cells, (necrotic bodies, NBs), as well as myelin debris. The mechanism by which the glia phagocytose and traffic NBs are not understood. Here, we show that OECs and SCs recognize phosphatidylserine on NBs, followed by engulfment and trafficking to endosomes and lysosomes. We also showed that both glia can phagocytose and process myelin debris. We compared the time-course of glial phagocytosis (of both NBs and myelin) to that of macrophages. Internalization and trafficking were considerably slower in glia than in macrophages, and OECs were more efficient phagocytes than SCs. The two glial types also differed regarding their cytokine responses after NB challenge. SCs produced low amounts of the pro-inflammatory cytokine TNF-α while OECs did not produce detectable TNF-α. Thus, OECs have a higher capacity than SCs for phagocytosis and trafficking, whilst producing lower amounts of pro-inflammatory cytokines. These findings suggest that OEC transplantation into the injured nervous system may lead to better outcomes than SC transplantation.

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Reovirus Strain-Dependent Inflammatory Cytokine Responses and Replication Patterns in a Human Monocyte Cell Line

Viral Immunology ◽

10.1089/vim.2006.19.546 ◽

2006 ◽

Vol 19 (3) ◽

pp. 546-557 ◽

Cited By ~ 4

Author(s):

Anthony L. Farone ◽

Sean M. O'donnell ◽

Chad S. Brooks ◽

Kristel M. Young ◽

Janene M. Pierce ◽

...

Keyword(s):

Cell Line ◽

Inflammatory Cytokine ◽

Human Monocyte ◽

Cytokine Responses ◽

Human Monocyte Cell Line ◽

Monocyte Cell ◽

Strain Dependent

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Entamoeba histolytica activation of caspase-1 degrades cullin that attenuates NF-κB dependent signaling from macrophages

PLoS Pathogens ◽

10.1371/journal.ppat.1009936 ◽

2021 ◽

Vol 17 (9) ◽

pp. e1009936

Author(s):

Attinder Chadha ◽

France Moreau ◽

Shanshan Wang ◽

Antoine Dufour ◽

Kris Chadee

Keyword(s):

Entamoeba Histolytica ◽

Inflammatory Cytokine ◽

Cytokine Production ◽

Inflammatory Responses ◽

Cysteine Proteinases ◽

Inflammatory Cytokine Production ◽

Downstream Signaling ◽

Caspase 1 ◽

Tnf Α ◽

Cullin 4A

While Entamoeba histolytica (Eh)-induced pro-inflammatory responses are critical in disease pathogenesis, the downstream signaling pathways that subsequently dampens inflammation and the immune response remains unclear. Eh in contact with macrophages suppresses NF-κB signaling while favoring NLRP3-dependent pro-inflammatory cytokine production by an unknown mechanism. Cullin-1 and cullin-5 (cullin-1/5) assembled into a multi-subunit RING E3 ubiquitin ligase complex are substrates for neddylation that regulates the ubiquitination pathway important in NF-κB activity and pro-inflammatory cytokine production. In this study, we showed that upon live Eh contact with human macrophages, cullin-1/4A/4B/5 but not cullin-2/3, were degraded within 10 minutes. Similar degradation of cullin-1/5 were observed from colonic epithelial cells and proximal colonic loops tissues of mice inoculated with live Eh. Degradation of cullin-1/5 was dependent on Eh-induced activation of caspase-1 via the NLRP3 inflammasome. Unlike cullin-4B, the degradation of cullin-4A was partially dependent on caspase-1 and was inhibited with a pan caspase inhibitor. Cullin-1/5 degradation was dependent on Eh cysteine proteinases EhCP-A1 and EhCP-A4, but not EhCP-A5, based on pharmacological inhibition of the cysteine proteinases and EhCP-A5 deficient parasites. siRNA silencing of cullin-1/5 decreased the phosphorylation of pIκ-Bα in response to Eh and LPS stimulation and downregulated NF-κB-dependent TNF-α mRNA expression and TNF-α and MCP-1 pro-inflammatory cytokine production. These results unravel a unique outside-in strategy employed by Eh to attenuate NF-κB-dependent pro-inflammatory responses via NLRP3 activation of caspase-1 that degraded cullin-1/5 from macrophages.

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HIV-1 Inhibits Phagocytosis and Inflammatory Cytokine Responses of Human Monocyte-Derived Macrophages to P. falciparum Infected Erythrocytes

PLoS ONE ◽

10.1371/journal.pone.0032102 ◽

2012 ◽

Vol 7 (2) ◽

pp. e32102 ◽

Cited By ~ 15

Author(s):

Louise E. Ludlow ◽

Jingling Zhou ◽

Emma Tippett ◽

Wan-Jung Cheng ◽

Wina Hasang ◽

...

Keyword(s):

Inflammatory Cytokine ◽

Human Monocyte ◽

Cytokine Responses ◽

Hiv 1

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Malaria Modifies Neonatal and Early-Life Toll-Like Receptor Cytokine Responses

Infection and Immunity ◽

10.1128/iai.00237-13 ◽

2013 ◽

Vol 81 (8) ◽

pp. 2686-2696 ◽

Cited By ~ 32

Author(s):

Komi Gbédandé ◽

Stefania Varani ◽

Samad Ibitokou ◽

Parfait Houngbegnon ◽

Sophie Borgella ◽

...

Keyword(s):

Immune Responses ◽

Early Life ◽

In Utero ◽

Innate Immune ◽

Innate Immune Responses ◽

Toll Like Receptor ◽

Content Type ◽

Cytokine Responses ◽

Increased Risk ◽

Tnf Α

ABSTRACTProtection from infections in early life relies extensively on innate immunity, but it is unknown whether and how maternal infections modulate infants' innate immune responses, thereby altering susceptibility to infections.Plasmodium falciparumcauses pregnancy-associated malaria (PAM), and epidemiological studies have shown that PAM enhances infants' susceptibility to infection withP. falciparum. We investigated how PAM-mediated exposuresin uteroaffect innate immune responses and their relationship with infection in infancy. In a prospective study of mothers and their babies in Benin, we investigated changes in Toll-like receptor (TLR)-mediated cytokine responses related toP. falciparuminfections. Whole-blood samples from 134 infants at birth and at 3, 6, and 12 months of age were stimulated with agonists specific for TLR3, TLR4, TLR7/8, and TLR9. TLR-mediated interleukin 6 (IL-6) and IL-10 production was robust at birth and then stabilized, whereas tumor necrosis factor alpha (TNF-α) and gamma interferon (IFN-γ) responses were weak at birth and then increased. In multivariate analyses, maternalP. falciparuminfections at delivery were associated with significantly higher TLR3-mediated IL-6 and IL-10 responses in the first 3 months of life (P< 0.05) and with significantly higher TLR3-, TLR7/8-, and TLR9-mediated TNF-α responses between 6 and 12 months of age (P< 0.05). Prospective analyses showed that higher TLR3- and TLR7/8-mediated IL-10 responses at birth were associated with a significantly higher risk ofP. falciparuminfection in infancy (P< 0.05). Neonatal and infant intracellular TLR-mediated cytokine responses are conditioned byin uteroexposure through PAM late in pregnancy. Enhanced TLR-mediated IL-10 responses at birth are associated with an increased risk ofP. falciparuminfection, suggesting a compromised ability to combat infection in early life.

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RIG-I Signaling via MAVS Is Dispensable for Survival in Lethal Influenza Infection In Vivo

Mediators of Inflammation ◽

10.1155/2018/6808934 ◽

2018 ◽

Vol 2018 ◽

pp. 1-14 ◽

Cited By ~ 3

Author(s):

Wenxin Wu ◽

Xiaoqiu Wang ◽

Wei Zhang ◽

Lili Tian ◽

J. Leland Booth ◽

...

Keyword(s):

Immune Responses ◽

Influenza A ◽

Influenza Infection ◽

Lavage Fluid ◽

Innate Immune ◽

Innate Immune Responses ◽

Downstream Signaling ◽

Cytokine Responses

Retinoic acid-inducible gene I (RIG-I) is an important regulator of virus-induced antiviral interferons (IFNs) and proinflammatory cytokines. It requires interaction with an adaptor molecule, mitochondrial antiviral-signaling protein (MAVS), to activate downstream signaling pathways. To elucidate the mechanism(s) by which RIG-I-dependent recognition of IAV infection in vivo triggers innate immune responses, we infected mutant mice lacking RIG-I or MAVS with influenza A virus (IAV) and measured their innate immune responses. As has previously been demonstrated with isolated deletion of the virus recognition receptors TLR3, TLR7, and NOD2, RIG-I or MAVS knockout (KO) did not result in higher mortality and did not reduce IAV-induced cytokine responses in mice. Infected RIG-I KO animals displayed similar lung inflammation profiles as did WT mice, in terms of the protein concentration, total cell count, and inflammatory cell composition in the bronchoalveolar lavage fluid. RNA-Seq results demonstrated that all types of mice exhibited equivalent antiviral and inflammatory gene responses following IAV infection. Together, the results indicated that although RIG-I is important in innate cytokine responses in vitro, individual deletion of the genes encoding RIG-I or MAVS did not change survival or innate responses in vivo after IAV infection in mice.

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Inhibition of Pro-Inflammatory Cytokine Secretion by Select Antioxidants in Human Coronary Artery Endothelial Cells

International Journal for Vitamin and Nutrition Research ◽

10.1024/0300-9831/a000520 ◽

2020 ◽

Vol 90 (1-2) ◽

pp. 103-112 ◽

Cited By ~ 1

Author(s):

Michael J. Haas ◽

Marilu Jurado-Flores ◽

Ramadan Hammoud ◽

Victoria Feng ◽

Krista Gonzales ◽

...

Keyword(s):

Endothelial Cells ◽

Ascorbic Acid ◽

Coronary Artery ◽

Inflammatory Cytokines ◽

Inflammatory Cytokine ◽

Culture Media ◽

Cytokine Secretion ◽

Human Coronary Artery ◽

Tnf Α ◽

Pro Inflammatory Cytokines

Abstract. Inflammatory and oxidative stress in endothelial cells are implicated in the pathogenesis of premature atherosclerosis in diabetes. To determine whether high-dextrose concentrations induce the expression of pro-inflammatory cytokines, human coronary artery endothelial cells (HCAEC) were exposed to either 5.5 or 27.5 mM dextrose for 24-hours and interleukin-1β (IL-1β), interleukin-2 (IL-2), interleukin-6 (IL-6), interleukin-8 (IL-8), and tumor necrosis factor α (TNF α) levels were measured by enzyme immunoassays. To determine the effect of antioxidants on inflammatory cytokine secretion, cells were also treated with α-tocopherol, ascorbic acid, and the glutathione peroxidase mimetic ebselen. Only the concentration of IL-1β in culture media from cells exposed to 27.5 mM dextrose increased relative to cells maintained in 5.5 mM dextrose. Treatment with α-tocopherol (10, 100, and 1,000 μM) and ascorbic acid (15, 150, and 1,500 μM) at the same time that the dextrose was added reduced IL-1β, IL-6, and IL-8 levels in culture media from cells maintained at 5.5 mM dextrose but had no effect on IL-1β, IL-6, and IL-8 levels in cells exposed to 27.5 mM dextrose. However, ebselen treatment reduced IL-1β, IL-6, and IL-8 levels in cells maintained in either 5.5 or 27.5 mM dextrose. IL-2 and TNF α concentrations in culture media were below the limit of detection under all experimental conditions studied suggesting that these cells may not synthesize detectable quantities of these cytokines. These results suggest that dextrose at certain concentrations may increase IL-1β levels and that antioxidants have differential effects on suppressing the secretion of pro-inflammatory cytokines in HCAEC.

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