Comparison of TLR2/1, NF-кB p105/50, NF-кB p65, and TNF-α expressions in the macrophages between multibacillary leprosy patients with and without erythema nodosum leprosum signifying innate immune system activity

ABSTRACT Contact with the human alveolar macrophage plays a key role in the innate immune response to Bacillus anthracis spores. Because there is a significant delay between the initial contact of the spore with the host and clinical evidence of disease, there appears to be temporary containment of the pathogen by the innate immune system. Therefore, the early macrophage response to Bacillus anthracis exposure is important in understanding the pathogenesis of this disease. In this paper, we studied the initial events after exposure to spores, beginning with the rapid internalization of spores by the macrophages. Spore exposure rapidly activated the mitogen-activated protein kinase signaling pathways extracellular signal-regulated kinase, c-Jun-NH2-terminal kinase, and p38. This was followed by the transcriptional activation of cytokine and primarily monocyte chemokine genes as determined by RNase protection assays. Transcriptional induction is reflected at the translational level, as interleukin-1α (IL-1α), IL-1β, IL-6, and tumor necrosis factor alpha (TNF-α) cytokine protein levels were markedly elevated as determined by enzyme-linked immunosorbent assay. Induction of IL-6 and TNF-α, and, to a lesser extent, IL-1α and IL-1β, was partially inhibited by the blockade of individual mitogen-activated protein kinases, while the complete inhibition of cytokine induction was achieved when multiple signaling pathway inhibitors were used. Taken together, these data clearly show activation of the innate immune system in human alveolar macrophages by Bacillus anthracis spores. The data also show that multiple signaling pathways are involved in this cytokine response. This report is the first comprehensive examination of this process in primary human alveolar macrophages.

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Differential Activation of Innate Immune Responses by Adenovirus and Adeno-Associated Virus Vectors

Journal of Virology ◽

10.1128/jvi.76.9.4580-4590.2002 ◽

2002 ◽

Vol 76 (9) ◽

pp. 4580-4590 ◽

Cited By ~ 235

Author(s):

Anne-Kathrin Zaiss ◽

Qiang Liu ◽

Gloria P. Bowen ◽

Norman C. W. Wong ◽

Jeffrey S. Bartlett ◽

...

Keyword(s):

Immune System ◽

Intravenous Administration ◽

Innate Immune System ◽

Innate Immune ◽

Target Cells ◽

Mrna Levels ◽

Dependent Manner ◽

Adeno Associated Virus ◽

Tnf Α ◽

Adenovirus Vectors

ABSTRACT Adenovirus vectors induce acute inflammation of infected tissues due to activation of the innate immune system and expression of numerous chemokines and cytokines in transduced target cells. In contrast, adeno-associated virus (AAV) vectors are not associated with significant inflammation experimentally or clinically. We tested the ability of AAV vectors to induce the expression of chemokines in vitro and to activate the innate immune system in vivo. In human HeLa cells and murine renal epithelium-derived cells (REC cells) the adenovirus vector AdlacZ induced the expression of multiple inflammatory chemokines including RANTES, interferon-inducible protein 10 (IP-10), interleukin-8 (IL-8), MIP-1β, and MIP-2 in a dose-dependent manner. The use of AAVlacZ did not induce the expression of these chemokines above baseline levels despite 40-fold-greater titers than AdlacZ and greater amounts of intracellular AAVlacZ genomes according to Southern and slot blot analysis. This finding confirmed that the lack of AAVlacZ induction of chemokine was not due to reduced transduction. In DBA/2 mice, the intravenous administration of 2.5 × 1011 particles of AAVlacZ resulted in the rapid induction of liver tumor necrosis factor alpha (TNF-α), RANTES, IP-10, MIP-1β, MCP-1, and MIP-2 mRNAs. However, 6 h following injection, chemokine mRNA levels returned to baseline. As expected, administration of 10-fold less AdlacZ caused an induction of liver TNF-α and chemokine mRNAs that persisted for more than 24 h posttransduction. Whereas intravenous administration of 2.5 × 1011 particles of AAVlacZ triggered a transient infiltration of neutrophils and CD11b+ cells into liver, this response stood in contrast to widespread inflammation and toxicity induced by AdlacZ. Kupffer cell depletion abolished AAVlacZ but not AdlacZ-induced chemokine expression and neutrophil infiltration. In summary, these results show that AAV vectors activate the innate immune system to a lesser extent than do adenovirus vectors and offer a possible explanation for the reduced inflammatory properties of AAV compared to adenovirus vectors.

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Arteriosclerosis: The Novel Finding of Biofilms and Innate Immune System Activity within the Plaques

Journal of Medical & Surgical Pathology ◽

10.4172/2472-4971.1000135 ◽

2016 ◽

Vol 01 (04) ◽

Cited By ~ 1

Author(s):

Herbert B Allen ◽

Jennifer Boles ◽

Diego Morales ◽

Shefali Ballal ◽

Suresh G Joshi

Keyword(s):

Immune System ◽

Innate Immune System ◽

Innate Immune ◽

The Novel ◽

System Activity

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Case Report: Innate Immune System Challenge Unleashes Paraneoplastic Neurological Autoimmunity

Frontiers in Neurology ◽

10.3389/fneur.2020.598894 ◽

2020 ◽

Vol 11 ◽

Author(s):

Mingqin Zhu ◽

Yuetao Ma ◽

Anastasia Zekeridou ◽

Vanda A. Lennon

Keyword(s):

Immune System ◽

Innate Immune System ◽

Protein Complexes ◽

Innate Immune ◽

Neurological Symptoms ◽

Autoimmune Response ◽

Tnf Α ◽

Bladder Instillation ◽

Molecular Patterns ◽

Symptoms And Signs

Paraneoplastic autoimmune neurological disorders reflect tumor-initiated immune responses against onconeural antigens. Symptoms and signs can affect the central and/or peripheral nervous systems, neuromuscular junction or muscle, and typically evolve subacutely before an underlying neoplasm is discovered. We describe four patients whose neurological symptoms were precipitated by potent innate immune system challenges: bladder instillation of BCG, tick bite and an “alternative cancer therapy” with bacterial extracts and TNF-α. We hypothesize that a tumor-initiated autoimmune response (evidenced by autoantibody profiles), pre-dating the immune system challenge, was unmasked or amplified in these patients by cytokines released systemically from innate immune cells activated by microbial pathogen-associated molecular patterns (PAMPs). The resultant upregulation of cognate onconeural peptides as MHC1 protein complexes on neural cell surfaces would render those cells susceptible to killing by CD8+ T cells, thus precipitating the patient's neurological symptoms.

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Mycobacterium avium Biofilm Attenuates Mononuclear Phagocyte Function by Triggering Hyperstimulation and Apoptosis during Early Infection

Infection and Immunity ◽

10.1128/iai.00820-13 ◽

2013 ◽

Vol 82 (1) ◽

pp. 405-412 ◽

Cited By ~ 25

Author(s):

Sasha J. Rose ◽

Luiz E. Bermudez

Keyword(s):

Immune System ◽

Mycobacterium Avium ◽

Innate Immune System ◽

Innate Immune ◽

Mononuclear Phagocytes ◽

Bacterial Killing ◽

Content Type ◽

Tnf Α

ABSTRACTMycobacterium aviumsubsp.hominissuisis an opportunistic human pathogen that has been shown to form biofilmin vitroandin vivo. Biofilm formationin vivoappears to be associated with infections in the respiratory tract of the host. The reasoning behind howM. aviumsubsp.hominissuisbiofilm is allowed to establish and persist without being cleared by the innate immune system is currently unknown. To identify the mechanism responsible for this, we developed anin vitromodel using THP-1 human mononuclear phagocytes cocultured with establishedM. aviumsubsp.hominissuisbiofilm and surveyed various aspects of the interaction, including phagocyte stimulation and response, bacterial killing, and apoptosis.M. aviumsubsp.hominissuisbiofilm triggered robust tumor necrosis factor alpha (TNF-α) release from THP-1 cells as well as superoxide and nitric oxide production. Surprisingly, the hyperstimulated phagocytes did not effectively eliminate the cells of the biofilm, even when prestimulated with gamma interferon (IFN-γ) or TNF-α or cocultured with natural killer cells (which have been shown to induce anti-M. aviumsubsp.hominissuisactivity when added to THP-1 cells infected with planktonicM. aviumsubsp.hominissuis). Time-lapse microscopy and the TUNEL (terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling) assay determined that contact with theM. aviumsubsp.hominissuisbiofilm led to early, widespread onset of apoptosis, which is not seen until much later in planktonicM. aviumsubsp.hominissuisinfection. Blocking TNF-α or TNF-R1 during interaction with the biofilm significantly reduced THP-1 apoptosis but did not lead to elimination ofM. aviumsubsp.hominissuis. Our data collectively indicate thatM. aviumsubsp.hominissuisbiofilm induces TNF-α-driven hyperstimulation and apoptosis of surveilling phagocytes, which prevents clearance of the biofilm by cells of the innate immune system and allows the biofilm-associated infection to persist.

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A Retrospective Study: Epidemiology, Onset, and Duration of Erythema Nodosum Leprosum in Surabaya, Indonesia

Berkala Ilmu Kesehatan Kulit dan Kelamin ◽

10.20473/bikk.v33.1.2021.8-12 ◽

2021 ◽

Vol 33 (1) ◽

pp. 8

Author(s):

Cindy Fransisca ◽

Iskandar Zulkarnain ◽

Evy Ervianti ◽

Damayanti Damayanti ◽

Maylita Sari ◽

...

Keyword(s):

Quality Of Life ◽

Retrospective Study ◽

Erythema Nodosum ◽

First Year ◽

Erythema Nodosum Leprosum ◽

Regular Control ◽

Leprosy Patients ◽

Multibacillary Leprosy

Background: Erythema nodosum leprosum (ENL) has a chronic and recurrent nature which could reduce patient’s quality of life in addition to the onset of ENL that occurs before, during, or after multidrug treatment, further emphasizing the importance of regular control and education.Purpose:This study aimed to evaluate the epidemiology, onset, duration, and recurrence of ENL. Methods:Data from medical records were obtained for a 3-year retrospective study of multibacillary leprosy patients at the Leprosy Division of the Dermatology and Venereology Outpatient Department, Dr. Soetomo General Hospital Surabaya, with a minimum of 2–5 years follow-up period.Result:The prevalence of ENL continued to increase almost every year especially in 2017 (32% in 2015; 32% in 2016; and 36% in 2017). ENL most often occurs during the first year of multi-drug therapy (MDT) administration followed by after the release from treatment (RFT) with the latest onset occurring 4 years after RFT. The majority of patients experienced chronic and recurrent reactions with the longest reactions lasting up to 4.5 years (55 months). Conclusion:Knowledge about the onset, duration, and recurrences of ENL are essential, and strict supervision for routine control shall be encouraged to increase the patients’ compliance so as to increase their quality of life.

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Tumor necrosis factor receptor 1-dependent depletion of mucus in immature small intestine: a potential role in neonatal necrotizing enterocolitis

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00550.2010 ◽

2011 ◽

Vol 301 (4) ◽

pp. G656-G666 ◽

Cited By ~ 59

Author(s):

Steven J. McElroy ◽

Lawrence S. Prince ◽

Jörn-Hendrik Weitkamp ◽

Jeff Reese ◽

James C. Slaughter ◽

...

Keyword(s):

Immune System ◽

Necrotizing Enterocolitis ◽

Premature Infants ◽

Goblet Cell ◽

Innate Immune System ◽

Goblet Cells ◽

Innate Immune ◽

Intestinal Mucus ◽

Tnf Α ◽

Small Intestinal

Necrotizing enterocolitis (NEC) is a leading cause of morbidity and mortality in premature infants. NEC is believed to occur when intestinal bacteria invade the intestinal epithelial layer, causing subsequent inflammation and tissue necrosis. Mucins are produced and secreted by epithelial goblet cells as a key component of the innate immune system and barrier function of the intestinal tract that help protect against bacterial invasion. To better understand the role of mucins in NEC, we quantified the number of mucus-containing small intestinal goblet cells present in infants with NEC and found they had significantly fewer goblet cells and Paneth cells compared with controls. To test whether inflammation has a developmentally dependent effect on intestinal goblet cells, TNF-α was injected into mice at various stages of intestinal development. TNF-α caused a loss of mucus-containing goblet cells only in immature mice and induced Muc2 and Muc3 mRNA upregulation only in mature ileum. Only minimal changes were seen in apoptosis and in expression of markers of goblet cell differentiation. TNF-α increased small intestinal mucus secretion and goblet cell hypersensitivity to prostaglandin E2 (PGE2), a known mucus secretagogue produced by macrophages. These TNF-α-induced changes in mucus mRNA levels required TNF receptor 2 (TNFR2), whereas TNF-α-induced loss of mucus-positive goblet cells required TNFR1. Our findings of developmentally dependent TNF-α-induced alterations on intestinal mucus may help explain why NEC is predominantly found in premature infants, and TNF-α-induced alterations of the intestinal innate immune system and barrier functions may play a role in the pathogenesis of NEC itself.

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Activation of the Innate Immune System by Treponema denticola Periplasmic Flagella through Toll-Like Receptor 2

Infection and Immunity ◽

10.1128/iai.00573-17 ◽

2017 ◽

Vol 86 (1) ◽

Cited By ~ 1

Author(s):

John Ruby ◽

Michael Martin ◽

Michael J. Passineau ◽

Valentina Godovikova ◽

J. Christopher Fenno ◽

...

Keyword(s):

Immune System ◽

Innate Immune System ◽

Innate Immune ◽

Treponema Denticola ◽

Toll Like Receptor ◽

Wild Type ◽

Content Type ◽

Tnf Α ◽

Toll Like Receptor 2 ◽

Periplasmic Flagella

ABSTRACTTreponema denticolais an indigenous oral spirochete that inhabits the gingival sulcus or periodontal pocket. Increased numbers of oral treponemes within this environment are associated with localized periodontal inflammation, and they are also part of an anaerobic polymicrobial consortium responsible for endodontic infections. Previous studies have indicated thatT. denticolastimulates the innate immune system through Toll-like receptor 2 (TLR2); however, the pathogen-associated molecular patterns (PAMPs) responsible forT. denticolaactivation of the innate immune system are currently not well defined. In this study, we investigated the role played byT. denticolaperiplasmic flagella (PF), unique motility organelles of spirochetes, in stimulating an innate immune response. Wild-typeT. denticolastimulated the production of the cytokines tumor necrosis factor alpha (TNF-α), interleukin-1β (IL-1β), IL-6, IL-10, and IL-12 by monocytes from human peripheral blood mononuclear cells, while its isogenic nonmotile mutant lacking PF resulted in significantly diminished cytokine stimulation. In addition, highly purified PF were able to dose dependently stimulate cytokine TNF-α, IL-1β, IL-6, IL-10, and IL-12 production in human monocytes. Wild-typeT. denticolaand the purified PF triggered activation of NF-κB through TLR2, as determined using a variety of TLR-transfected human embryonic 293 cell lines, while the PF-deficient mutants lacked the ability to stimulate, and the complemented PF-positiveT. denticolastrain restored the activation. These findings suggest thatT. denticolastimulates the innate immune system in a TLR2-dependent fashion and that PF are a key bacterial component involved in this process.

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