Microglia: Giving out dangerous signals - Cell Signaling Update - Signaling Gateway

"The release of heat-shock protein HSP60 from injured neurons activates Toll-like receptor 4 (TLR4) signaling, which stimulates microglia and facilitates neurodegeneration."

Read more: Microglia: Giving out dangerous signals - Cell Signaling Update - Signaling Gateway:

LPS stimulates nitric oxide synthase-2 expression in murine skeletal muscle and C(2)C(12) myoblasts via Toll-like receptor-4 and c-Jun NH(2)-terminal kinase pathways.

"Frost, R. A., Nystrom, G. J., and Lang, C. H. (2004). Lipopolysaccharide stimulates nitric oxide synthase-2 expression in murine skeletal muscle and c(2)c(12) myoblasts via toll-like receptor-4 and c-jun nh(2)-terminal kinase pathways. American journal of physiology. Cell physiology, 287(6)."

CiteULike: Lipopolysaccharide stimulates nitric oxide synthase-2 expression in murine skeletal muscle and C(2)C(12) myoblasts via Toll-like receptor-4 and c-Jun NH(2)-terminal kinase pathways.:

Release of Prostaglandin E2 and Nitric Oxide from Spinal Microglia Is Dependent on Activation of p38 Mitogen-Activated Protein Kinase.

TLR4: receptors that recognize liposaccharides on gram (-) bacteria that once activated trigger a number of different immune events.

"Our findings suggest that (a) activation of spinal microglia via TLR4 but not NK1 receptors produces PGE(2) and NO release from these cells; (b) the evoked PGE(2) release is generated by both COX-1 and COX-2, and (c) the COX-PGE(2) pathway is regulated by p38 and NOS2."

CiteULike: Release of Prostaglandin E2 and Nitric Oxide from Spinal Microglia Is Dependent on Activation of p38 Mitogen-Activated Protein Kinase.:

The Transcription Factor Nrf2 Is a Therapeutic Target against Brain Inflammation -- Innamorato et al. 181 (1): 680 -- The Journal of Immunology

The Transcription Factor Nrf2 Is a Therapeutic Target against Brain Inflammation -- Innamorato et al. 181 (1): 680 -- The Journal of Immunology: "Model proposed for modulation of microglia by the Nrf2/HO-1 axis. Pathogenic or neurotoxic insults (LPS) interact with pattern recognition receptors (TLR4) and trigger the early release of NADPH oxidase-mediated ROS and other proinflammatory factors. The increase of intracellular ROS is then detected by Nrf2, guardian of redox homeostasis, which activates a set of antioxidant and anti-xenobiotic genes, including HO-1. This late antioxidant response restores the redox balance, inhibits NADPH oxidase and down-regulates TLR4, driving active microglia back to the resting state. Genetic variability in key antioxidant enzymes, environmental alterations, or just the normal decline of redox homeostasis that occurs with aging leads to inefficient redox control and reduced capacity to down-modulate active microglia. This fact results in microglial activation and brain damage. Pharmacologic action on the Nrf2/HO-1 axis reinforces or restores microglial redox control, strengthens the negative loop, and assists in reduction of neuroinflammation."

Systemic Toll-Like Receptor Stimulation Suppresses Experimental Allergic Asthma and Autoimmune Diabetes in NOD Mice.

CiteULike: Systemic Toll-Like Receptor Stimulation Suppresses Experimental Allergic Asthma and Autoimmune Diabetes in NOD Mice.: "systemic administration of TLR ligands can suppress both allergic and autoimmune responses. They provide a plausible explanation for the hygiene hypothesis. They also open new therapeutic perspectives for the prevention of these pathologies."

HO-1 upregulation improves lipopolysaccharide-induced acute lung injury involving suppression of macrophage migration inhibitory factor.

CiteULike: Heme oxygenase-1 upregulation improves lipopolysaccharide-induced acute lung injury involving suppression of macrophage migration inhibitory factor.: "cytoprotective functions of HO-1 in LPS-induced lung injury are associated with negative regulation of lung MIF and TLR4-induced inflammatory response."

TLRs Regulates Reactions to Particulate Matter and Other Contaminant Considerations~!

In this article, the author explains "it is plausible that PM2.5 contains bacterial or mycoplasma lipoproteins, which are known activators of TLR2 . Because PM2.5 contain high concentrations of a large number of metals. One or more of these metals could be involved in increased TLR2- mediated cytokine production triggered by microbial lipoprotein constituents of the PM2.5. In this regard, it is interesting that TLR2 has been implicated in proinflammatory cytokine expression by airway epithelial cells stimulated with air PM containing high amounts of metals. Another possibility is that PM2.5 cytokine-inducing effects are mediated by an indirect mechanism, via the generation of endogenous “danger” host molecules activating macrophages via TLR2."

Note: Recent findings by Notch show a potentiation effect between cyanobacteria and heavy metals and thus support an important mechanism although the mechanism remains to be elicited. In addition, one must always consider alterations in methylation which can be caused by endotoxin and heavy metals. Walsh and Usman demonstrated that in autism there is alterations in the functioning of metallotheinin protein which modulates and detoxifies metals. (Treat Autism and AD/HD, Wright) In other blogs, we have explained that metallotheinin inhibits GSK-3b (Wang)which can turn off the Nrf2 antioxidant system. This could explain why there are reports that the antioxidant system is negatively effected by metals (and by endotoxin)and thus, one must also consider that in mixed environmental pollutants, there is a reduction of function of this system. In addition, there is also potential that the AhR and metals interact to influence antioxidant and detoxification. These interactions of metals and the AhR are currently being investigated through a number of projects. (Korashy) Further study may shed more light on the interactions of the Nrf2 and AhR gene batteries and how they are effected by metals from environmental exposures.

Shoenfelt, J., Mitkus, R. J., Zeisler, R., Spatz, R. O., Powell, J., Fenton, M. J., Squibb, K. A., and Medvedev, A. E. (2009). Involvement of tlr2 and tlr4 in inflammatory immune responses induced by fine and coarse ambient air particulate matter. Journal of Leukocyte Biology, 86. http://www.citeulike.org/user/HEIRS/article/7367529

Vita. Hesham Korashy, PhD. Retrieved on June 29, 2010.
http://faculty.ksu.edu.sa/hkorashy/Pages/index.aspx

Notch, E. G., Miniutti, D. M., Berry, J. P., and Mayer, G. D. (2010). Cyanobacterial lps potentiates cadmium toxicity in zebrafish (danio rerio) embryos. Environmental toxicology.
http://www.citeulike.org/user/HEIRS/article/7367622

Heavy Metals. Treat Autism and ADHD. Retrieved on June 30, 2010. http://www.treatautism.ca/?page_id=126

Wang et al. Inactivation of GSK-3 by Metallothionein PreventsDiabetes-Related Changes in Cardiac EnergyMetabolism, Inflammation, Nitrosative Damage, and Remodeling. Diabetes. June 2009. Pgs. 1391-1402.

Wright, R. O. and Baccarelli, A. (2007). Metals and neurotoxicology. The Journal of Nutrition.
http://www.citeulike.org/user/HEIRS/article/7367642

Commensal microflora induce host defense and decrease bacterial translocation in burn mice through toll-like receptor 4

"that commensal microflora induce host defense and decrease bacterial translocation in burn mice through toll-like receptor"

CiteULike: Commensal microflora induce host defense and decrease bacterial translocation in burn mice through toll-like receptor 4:

Regulatory T Cells and Inflammation in the Intestinal Tract

Background: It has been proposed that environmental pollutants may dysregulate Treg suppressive function and may therefore contribute to environmental illness.

"The enterocolitis in the Il10–/– mice is largely attributed to dysfunctional Tregs. As in many other models of intestinal inflammation, the inflammatory response in the intestinal mucosa in this model of colitis depends on luminal bacteria and/or their inflammatory components....In addition, this author reported that mice that were null for both IL10 and TLR4 have increased inflammation and is similar to the findings of increased inflammation from Helicobacter in Il10 -/- and TLR4 -/- animals. These findings suggest a positive role of TLR4 on the regulatory function of Tregs in intestinal inflammation."


González-Navajas, J. M., Fine, S., Law, J., Datta, S. K., Nguyen, K. P., Yu, M., Corr, M., Katakura, K., Eckman, L., Lee, J., and Raz, E. (2010). Tlr4 signaling in effector cd4+ t cells regulates tcr activation and experimental colitis in mice. Journal of Clinical Investigation.
http://www.citeulike.org/user/HEIRS/article/6488590?show_msg=already_posted

Wine Component Reduces Inflammatory Pathway Mediation by Endotoxin

Summary: Resveratrol counteracted LPS effect by decreasing CD14 and IRAK1 expression but unexpectedly increased the p38 MAPK protein phosphorylation. Altogether, our data highlighted the functionality of the TLR4-Myd88 signaling pathway in LPS prooxidant effect using non myeloid cells.

Sebai, H., Ristorcelli, E., Sbarra, V., Hovsepian, S., Fayat, G., Aouani, E., and Lombardo, D. (2009). Protective effect of resveratrol against lps-induced extracellular lipoperoxidation in ar42j cells partly via a myd88-dependent signaling pathway. Archives of biochemistry and biophysics. http://www.citeulike.org/user/HEIRS/article/6457832

Chemical Sensitivity: Possible Reason Why People Get Sick When They Smell Odors

Background: Inflammatory conditions in the intestinal tract such as would occur from colitis (or LPS) may cause alterations in signaling by serotonin-producing enterochromaffin cells. A recent experiment shows serotonin mediates inflammatory cytokines and the immune system through the NF-kappaB pathway which can also regulate CYP transcription. (Zordofsky) These cells also contain TLR receptors and therefore ligands of TLR may excite these cells  and it has been suggested that TLR signaling stimulates neurohormones which have been shown to alter normal immune responses. Interestingly, this author also notes that IBS and enteritis increases the numbers of enteroendocrine cells but there is conflicting evidence on whether this is consistent in inflammatory disease. Admittedly, there is a lot to learn about how activation of these cells impact specific immune functions but identifies an important role  of bacteria  regulation in inflammation.(Bugonovic)

In addition, activation of TRP channels have been suggested as having a role in MCS. (Pall) Doihara shows that activation of these receptors may alter intestinal function and this is achieved through TRPV1 acting through a serotoninergic pathway. TRPV1 ligands can be produced endogenously and inflammatory processes within the intestinal tract may increase the production of these ligands that stimulate TRPV1 activation of enterochromaffin activity and serotonin secretion. (Nozawa) As Rhee explains, enterochromaffin cells provide the means for communication between the intestinal tract and the central nervous system. Disruption of these cells may also disrupt the interactions that exist between the microflora and the nervous system that may lead to altered responses in the nervous system. Also important is that regulation of immunity by enterochromaffin cells may be different depending on the T-cell environment which may be crucial to understanding alterations of immunity in environmental illness considering it has been proposed that many of the responses may have more of an autoimmune type presentation. (Motomura)

Many people with sensitivities to toxicants in the environment have pointed out that upon smelling an odor or upon exposure that they may feel sick or have "intestinal discomfort" that results in diarrhea or noticeable dysregulation of the intestinal tract.  A study that was published in 2007 helps to explain what might cause this condition. Serotonin is a hormone that assists in the regulation of the activities in the intestinal tract. Researchers have found that in the human intestinal tract serotonin and nasal olfactory receptors are expressed by enterochromaffin cells. Braun determined that serotonin is released when odorants in spices, fragrances, detergents and cosmetics are presented. The presentation of odorant ligands result in a calcium flux in the cell that results in this release. As the author notes, these chemicals that activate the odorant receptors may play an important role in vomiting, diarrhea and irritable bowel syndrome because the hormone serotonin controls modulation of the intestinal tract. Thus therapies that target the olfactory receptors may be useful in the treatment of gastrointestinal diseases and motility disorders. In addition, while the author does not mention this --- altered signaling by these receptors may be influential in conditions such as multiple chemical sensitivity and certain panic behaviors.

Braun, T., Voland, P., Kunz, L., Prinz, C., and Gratzl, M. (2007). Enterochromaffin cells of the human gut: Sensors for spices and odorants. Gastroenterology, 132(5):1890-1901. http://www.citeulike.org/user/HEIRS/article/4184948
Ghia, J.-E. E., Li, N., Wang, H., Collins, M., Deng, Y., El-Sharkawy, R. T., Côté, F., Mallet, J., and Khan, W. I. (2009). Serotonin has a key role in pathogenesis of experimental colitis. Gastroenterology, 137(5):1649-1660. http://www.citeulike.org/user/HEIRS/article/6444407
Doihara, H., Nozawa, K., Kawabata-Shoda, E., Kojima, R., Yokoyama, T., and Ito, H. (2009). Trpa1 agonists delay gastric emptying in rats through serotonergic pathways. Naunyn-Schmiedeberg's archives of pharmacology, 380(4):353-357. http://www.citeulike.org/user/HEIRS/article/5382577
Rhee, S. H., Pothoulakis, C., and Mayer, E. A. (2009). Principles and clinical implications of the brain-gut-enteric microbiota axis. Nature reviews. Gastroenterology & hepatology, 6(5):306-314. http://www.citeulike.org/user/HEIRS/article/6444410
Pall, M. L. and Anderson, J. H. (2004). The vanilloid receptor as a putative target of diverse chemicals in multiple chemical sensitivity. Archives of environmental health, 59(7):363-375. http://www.citeulike.org/user/HEIRS/article/5911051
Zordoky, B. N. and El-Kadi, A. O. (2009). Role of nf-kappab in the regulation of cytochrome p450 enzymes. Current drug metabolism, 10(2):164-178. http://www.citeulike.org/user/HEIRS/article/4680706
Motomura, Y., Ghia, J. E., Wang, H., Akiho, H., El-Sharkawy, R. T., Collins, M., Wan, Y., Mclaughlin, J. T., and Khan, W. I. (2008). Enterochromaffin cell and 5-hydroxytryptamine responses to the same infectious agent differ in th1 and th2 dominant environments. Gut, 57(4):475-481. http://www.citeulike.org/user/HEIRS/article/3346104
Nozawa, K., Kawabata-Shoda, E., Doihara, H., Kojima, R., Okada, H., Mochizuki, S., Sano, Y., Inamura, K., Matsushime, H., Koizumi, T., Yokoyama, T., and Ito, H. (2009). Trpa1 regulates gastrointestinal motility through serotonin release from enterochromaffin cells. Proceedings of the National Academy of Sciences of the United States of America, 106(9):3408-3413. http://www.citeulike.org/user/HEIRS/article/4184960#
Bogunovic, M., Dave, S. H., Tilstra, J. S., Chang, D. T. W., Harpaz, N., Xiong, H., Mayer, L. F., and Plevy, S. E. (2007). Enteroendocrine cells express functional toll-like receptors. Am J Physiol Gastrointest Liver Physiol, 292(6):G1770-1783. http://www.citeulike.org/user/HEIRS/article/6444698
 



Defining Multiple Chemical Sensitivity

TLR as Inflammatory Mediators: Why Ozone and MCS Do Not Mix

Several recent observations have revealed possible routes of physiological consequences of toxicant exposure (ie ozone) that may be related to symptoms of MCS. It has been suggested activation of TRP channels may play an important role causal in MCS. (Pall) Bessac and Jordt write, "that both the TRPA1 and TRPV1 receptor may contribute to chemical hypersensitivity, chronic cough, and airway inflammation in asthma, COPD, and reactive airway dysfunction syndrome" and other reports link TRPA1 to asthma.(Drug Disovery) Activations of these receptors will increase their expression, therefore, increasing the likelihood of activation (and symptoms) by exposures that activate them. Or on the other hand, Bessac writes, cross-desensitization exists by one chemical may desensitize it to another. As we noted over a year ago, changes in these receptors can occur by interactions with other proteins including IGF-1 and inflammatory cytokines that may alter these receptors functioning which may cause "aberrant signaling".

Recently it has been demonstrated that ozone activates TRPA1 channels and TRPA1 channels have been shown to be upregulated by the inflammatory cytokine MCP-1/ pathway which has been discussed at length in other blogs. Ozone and smoking promote a process called oxidation of phospholipids (oxPL) that generates ROS from NADPH oxidase activation, increase MCP-1, negatively regulate Nrf2 and are associated with autoimmune diseases such as lupus, RA and Parkinson's disease. OxPL are generated during inflammatory conditions and inhibit the full differention of dendritic cells and therefore restrict normal adaptive immune response. (Bluml) Recently other research has provided evidence that additional ozone reactions can be caused from abnormal enzymatic actions of glutathione which, by he way, is also regulated by Nrf2 through other proteins. In addition, ozone contributes to airway hypersensitivity and hyperresponsiveness through the modulation of TLR receptors and other green house gases may play a part in the "learned response" tied possibly to physiological response in MCS, may  potentiate the effects of lead-based paint and increase related health risks and cause panic-like behavior.

Just in case you have heard that ozone generators are physiologically calming...well, according to the research, quite the opposite seems to be true. For instance, as new study shows there is a sensor in the brain for CO2, another greenhouse gas, that will cause panic-attacks. Such behaviors are crucial for animals for survival to be able to "sense" and prevent biological suffocation and "aberrant signaling" of TLR receptor may decrease the threshold of activation of these sensors. Keely explains that "epithelial hypoxia" in the gut results in a 40-fold increase in translocation of gram-negative bacteria, regardless of intestinal barriar function. In the gut, hypoxia is associated with acute and chronic inflammation (ie IBD) and its presence initiates factors that exploits the intestinal environment to achieve the translocation process. One can assume that similar sensory processes that activate panic or flight response may be present in other tissues including the lungs and gut. Additionally, it has been demonstrated that viruses activate TLR receptors but the mechanism is slightly different.

TLR4 receptors recognize LPS endotoxin which is the a component of the wall of gram-negative bacteria. Several reports now suggest that a route of CFS is endotoxin exposure.Endotoxin is the result of lysis of bacteria from immune cells and therefore, will be present whereever there is inflammation. Of course, minimizing exposures that contain bacteria is one way to reduce TLR signaling. There are other TLR receptors that also initiate immune responses to other contaminants.   Recent evidence has demonstrated that saturated fat "angers" the immune system by interacting with TLR4 but the exact process of how saturated fat does this is unclear. Cani has noted that LPS in high-fat diets is 2 to 3 times greater and that LPS-containing  proportion is greater in the high-fat diet gut.  Other conditions may favor altered TLR4 signaling and because they initiate a variety of events inside the cell, the absence or dysregulation of the antioxidant system can lead to an exacerbation of inflammatory events because it modulates cytokines production such as pro-inflammatory Il-1 and Tnf-a and the anti-inflammatory cytokine Il-10 which modulates sickness syndrome. The antioxidant system Nrf2 supports other proteins in mitochondrial biogenesis which it has been reported that exposure to chemicals has an effect on cellular respiration and alters mitochondrial function.  Altered TLR signaling also may contribute to neuropathic pain. Other effects include alteration in neurotransmission such as dopamine which may contribute to Parkinson's disease and other neurodegenerative diseases.

I have written several essays on TLR receptors and how they interact with the immmune system from different environmental toxicants which can be read here. Also, to read citations for this article click here.

Synergistic effect of two oxidative stress-related genes (heme oxygenase-1 and gsk3β) on the risk of parkinson's disease.

Background: Nrf2 is a regulator of the antioxidant system including the production of HO-1 that provides protection against a number of toxic insults and GSK-3b acts as an on/off switch of that system. In addition, it has been shown that GSk-3b regulates the inflammatory response of LPS endotoxin through modulation of toll receptors. TLR4 has been shown to be instrumental in initializing and maintaining neuropathic pain.

Infante, J., García-Gorostiaga, I., Sánchez-Juan, P., Sierra, M., Martín-Gurpegui, J. L., Terrazas, J., Mateo, I., Rodríguez-Rodríguez, E., Berciano, J., and Combarros, O. (2009). Synergistic effect of two oxidative stress-related genes (heme oxygenase-1 and gsk3β) on the risk of parkinson's disease. European Journal of Neurology, 9999(9999). http://www.citeulike.org/user/HEIRS/article/6426071


HEIRS Library Tags: GSK-3b, HO-1

Supplemental citation: Martin, M., Rehani, K., Jope, R. S., and Michalek, S. M. (2005). Toll-like receptor-mediated cytokine production is differentially regulated by glycogen synthase kinase 3. Nature immunology, 6(8):777-784. http://www.citeulike.org/user/HEIRS/article/2605
Hutchinson, M. R., Zhang, Y., Brown, K., Coats, B. D., Shridhar, M., Sholar, P. W., Patel, S. J., Crysdale, N. Y., Harrison, J. A., Maier, S. F., Rice, K. C., and Watkins, L. R. (2008). Non-stereoselective reversal of neuropathic pain by naloxone and naltrexone: involvement of toll-like receptor 4 (tlr4). The European journal of neuroscience, 28(1):20-29. http://www.citeulike.org/user/HEIRS/article/2997140

). Cigarette smoking blocks the protective expression of nrf2/are pathway in peripheral mononuclear cells of young heavy smokers favouring inflammation

Garbin, U., Pasini, A. F., Stranieri, C., Cominacini, M., Pasini, A., Manfro, S., Lugoboni, F., Mozzini1, C., Guidi, G., Faccini, G., and Cominacini, L. (2009). Cigarette smoking blocks the protective expression of nrf2/are pathway in peripheral mononuclear cells of young heavy smokers favouring inflammation. PLoS ONE, 4(12).

Expression of tlr4 and cd14 in the central nervous system (cns) in a mptp mouse model of parkinson's-like disease

Panaro, M. A., Lofrumento, D. D., Saponaro, C., De Nuccio, F., Cianciulli, A., Mitolo, V., and Nicolardi, G. (2008). Expression of tlr4 and cd14 in the central nervous system (cns) in a mptp mouse model of parkinson's-like disease. Immunopharmacology and Immunotoxicology, 30(4):729-740. http://www.citeulike.org/user/HEIRS/article/6389780

More on TLR4 and LPS

Youn, H. S. S., Kim, Y. S. S., Park, Z. Y. Y., Kim, S. Y. Y., Choi, N. Y. Y., Joung, S. M. M., Seo, J. A., Lim, K.-M. M., Kwak, M.-K. K., Hwang, D. H., and Lee, J. Y. Y. (2009). Sulforaphane suppresses oligomerization of tlr4 in a thiol-dependent manner. Journal of immunology (Baltimore, Md. : 1950). http://www.citeulike.org/user/HEIRS/article/6334999

Yamawaki, Y., Kimura, H., Hosoi, T., and Ozawa, K. (2009). Myd88 plays a key role in lps-induced stat3 activation in the hypothalamus. American journal of physiology. Regulatory, integrative and comparative physiology. http://www.citeulike.org/user/HEIRS/article/6334989

Chhikara, M., Wang, S., Kern, S. J., Ferreyra, G. A., Barb, J. J., Munson, P. J., and Danner, R. L. (2009). Carbon monoxide blocks lipopolysaccharide-induced gene expression by interfering with proximal tlr4 to nf-kappab signal transduction in human monocytes. PloS one, 4(12). http://www.citeulike.org/user/HEIRS/article/6334984

Dessing, M. C., Hirst, R. A., de Vos, A. F., and van der Poll, T. (2009). Role of toll-like receptors 2 and 4 in pulmonary inflammation and injury induced by pneumolysin in mice. PloS one, 4(11). http://www.citeulike.org/user/HEIRS/article/6334977

Expression of TLR4 and CD14 in the Central Nervous System (CNS) in a MPTP Mouse Model of Parkinson's-Like Disease

Title: Expression of tlr4 and cd14 in the central nervous system (cns) in a mptp mouse model of parkinson's-like disease.

Summary: Results demonstrated an augmented expression of both CD14 and TLR4 in the substantia nigra of mice treated with MPTP in comparison to untreated animals, suggesting that the endotoxin receptors are over expressed in different manner in specific areas of the CNS during Parkinson's-like disease.

Panaro‌, M. A., Lofrumento, D. D., Saponaro‌, C., De Nuccio, F., Cianciulli, A., Mitolo, V., and Nicolardi‌, G. (2008). Expression of tlr4 and cd14 in the central nervous system (cns) in a mptp mouse model of parkinson's-like disease. Immunopharmacology and Immunotoxicology, 30(4):729-740. http://www.citeulike.org/user/HEIRS/article/6334780

A conjugated linoleic acid-enriched beef diet attenuates lipopolysaccharide-induced inflammation in mice in part through ppargamma-mediated suppression of toll-like receptor 4

HEIRS Environmental Illness Research Blog: Why Endotoxin Can Increase Pain,Chemical and Mold Sensitivity and Causes Sickness Behavior!


Inflammatory mediators can reduce the expression of PPAR-gamma!


Reynolds, C. M., Draper, E., Keogh, B., Rahman, A., Moloney, A. P., Mills, K. H., Loscher, C. E., and Roche, H. M. (2009). A conjugated linoleic acid-enriched beef diet attenuates lipopolysaccharide-induced inflammation in mice in part through ppargamma-mediated suppression of toll-like receptor 4. The Journal of nutrition. http://www.citeulike.org/user/HEIRS/article/6007864

Why Endotoxin Can Increase Pain,Chemical and Mold Sensitivity and Causes Sickness Behavior!

Toll-like receptors: are a class of proteins that play a key role in the innate immune system. (Wipedia)

Background: Binding to toll-like receptors may initiate inflammatory responses including the production of chemokines. They mainly signal through NF-kappaB and increase transcription of inflammatory proteins Il-1b, Tnf-a, CCL2 (MCP-1) etc. (Devaraj) These are receptors that are highly expressed and are considered to be a link between diet and metabolism and are implicated as important factors in a number of health conditions including lupus, atherosclerosis and diabetes. (Dasu) We have noted in other blogs that they may play an important role in conditions that are most often considered "environmental illnesses" including chronic fatigue syndrome and/or contribute to symptoms of chemical sensitivity. To put it simply, toll-like receptors are considered signal transducers that initiate inflammatory processes and two common ligands are LPS endotoxin (which has been implicated in CFS) and saturated fatty acids. The ligands that bind TLR contain a "molecular pattern" the TLR recognizes and may be present in microbial and non-microbial agents or may be responsive to signals generated at the site of inflammation or from endogenously-produced proteins like heat shock proteins. Thus, their activites become a concern when ever pathogenic exposure or inflammation may be present.

The distribution of the toll-like receptors is different in different tissues but include epithelia and endothelia in the intestinal tract, the respiratory tract, the blood-brain barrier, etc. It is now believed that there is a commensal relationship that exists between the gut microbiota and TLR to maintain gut integrity (Hopkins) and may involve epigenetic influences and down-regulation of TLR gene transcription. (Takahashi)    It has been determined that TLR2 and TLR4 bind to gram positive and negative bacteria respectively. However, the production of one type of TL receptor may induce the induction of the other. Devaraj demonstrated that type-1 diabetes and increased levels of IL-1b and TNF-a is correlated with expression of TLR and also endotoxin "contribute to the inflammatory burden by activating TLR receptors" and suggests their instrumental in diabetes pathology. In addition, it has also been determined that high glucose levels can stimulate the expression of these receptors in monocytes. While toll-like cells are involved in cytokine production and cell activation, the inflammatory responses initiated by activation of receptors may last long after the initial stimulus is gone or may potentiate the inflammatory responses of other insults. It may seem beneficial to blunt the responses of TLR, but it may be more harmful by making the organism more susceptible to infection.(Hopkins) On the other hand, aberrant signaling from TLR can lead to autoimmune-type conditions as we noted above.

Other studies demonstrate that the expression of TLR are widespread are can activate microglia and astocytes and play a role in neuroinflammatory responses. Microglia are sensory-type cells that are the main source of inflammatory mediators in the nervous system.  Some studies show that TLR activation of microglia leads to an increase in NO, superoxide and other cytokines and that TLR-deficient microglia demonstrated a significant reduction in several types of inflammatory responses. Obata confirmed TLR3 has an important role in the development of tactile allodynia after nerve injury and blocking these receptors may provide effective treatment for neuropathic pain which has been linked to fibromyalgia. Recent findings are suggestive of the notion that fibromyalgia is a "disorder of central processing with neuroregulation/
transmission dysfunction" (NFA) and TLR4 may initiate an inflammatory profile through NF-kappaB at least in a subset of fibromyalgia patients. In one model of neuropathic pain, tactile allodynia was "abrogated" in CCR2 mice which is the receptor for CCL2 (MCP-1), the inflammatory cytokines activated by NF-kappaB and has been suggested as a possible marker for fibromyalgia. It also plays a very important role in the development of neuroinflammation via the TNF-a/CCL2/CCR2 pathway. From this, it has been suggested that activation of immune cells and microglia peripherally and in neurons may contribute to inflammatory and neuropathic pain states and (Abbadie) importantly, it is now understood that TLR agonists modulates CCR2 expression and CCL2 responsiveness. (Souto, Parker) Jo et al explains peripheral injuries that lead to neuropathic states causes pathology not only in the damaged nerves but also causes changes in the central processing of sensory information and glial activation may facilitate "noxious signal transduction" even after the initial injury has healed. Therefore, TLR may not only initiate neuropathic pain but also maintain it.  Experts believe nociceptive behavior may influence symptoms of MCS (Pall) and it has been demonstrated pain caused by bacterial infection may be generated through activation of nociceptors via the TLR in neurons. (Wabachi) In addition, TLR responses play a role in viral and parasitic infections, multiple sclerosis, exacerbate injury in ischemia (Kielian) and chronic activation of TLR is associated with anxiety, avoidance and sickness behavior (Hudson) and increased sensitivity to other toxicants (Pestka).

Other reports show in epithelial cells, TLR mediate immune cells production from exposure to particulate matter and contribute to airway hypersensitivity from exposure to ozone. (Williams) More recently, it has been shown that the aryl hydrocarbon receptor (AhR), which plays a role in the detoxification of polyaromatic hydrocarbons and halogenated hydrocarbons, negatively regulates TLR signaling. Animals that are deficient in the AhR exhibit exaggerated inflammatory responses including significant elevations in TNF-a and IL-6 and are highly susceptible to septic shock. (Ogawa, Kimura) We have expressed the belief that the abnormal functioning of the AhR may contribute to environmental illnesses including multiple chemical sensitivity because of its role in detoxification and its relationship to the antioxidant system regulator Nrf2. The Nrf2 protects neurons and other cells against oxidative and environmental insults in primary and secondary injury. TLR activates NF-kappaB through the universale adaptor protein MyD88 and it has been shown that Nrf2 has a "global influence" on MyD88-dependant and independant signaling. Deficiency of Nrf2 dysregulated expression of genes that encode molecular components of innate immunity (e.g., peptidoglycan-recognition proteins, proinflammatory cytokines, chemokines, and adhesion molecules and receptors." (Thimmulappa)

Study Highlight: Pestka provides evidence that the preexposure of a TLR agonist such as LPS endotoxin increases the inflammatory response of DON, a mycotoxin. This response which included production of IL-1b, Il-6, and TNF-a was at levels higher than either produced alone. During the study, preexposure to other TLR agonists, also increased the pro-inflammatory responses of DON in a similar manner as LPS. In addition, similar heightened responses occured from LPS preexposure of TLR and subsequent effects of microbial and non-microbial "agents" including satratoxin, Shiga toxin, zearalenone and toxicants such as nickel chloride, triphenyltin, dinitrochlorobenzene (a known irritant) and dioxin. It has been concluded from this study that prior exposure to TLR agonists (ie endotoxin, saturated fat and others) "might render macrophages highly sensitive to subsequent induction of proinflammatory gene expression by xenobiotics with diverse mechanisms of action." (Pestka)

Notes:

• An important source of bacterial and endotoxin contamination is from our drinking water. Find out more about the importance of healthy water with a clip from the Dr. Oz Show. Other main sources include from the air we breath.
• IRAK-1 is necessary for LPS-mediated suppression of PPARalpha and PGC-1alpha, nuclear factors essential for the expression of anti-oxidative enzymes such as GPX3 and catalase (Maitra) "ROS trafficking(NADPH oxidase) mediates LPS/TLR signals in neutraphils and downstream targets including IRAK-1. Deficiency of Nrf2 predisposes neutraphils to greater responsiveness to LPS which is mediated by increased ROS generation. (Thimmulappa)

Reference Resource:

• Toll-like receptor (TLR)-mediated biology (Hopkins)
  

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Original document and citations can be accessed here.

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The interaction between toll-like receptors and fatty acids "engage" the immune complex Il-1b and its receptor to activate other inflammatory processes in the pancreas.



Böni-Schnetzler, M., Boller, S., Debray, S., Bouzakri, K., Meier, D. T., Prazak, R., Kerr-Conte, J., Pattou, F., Ehses, J. A., Schuit, F. C., and Donath, M. Y. (2009). Free fatty acids induce a proinflammatory response in islets via the abundantly expressed interleukin-1 receptor i. Endocrinology, pages en.2009-0543+. http://www.citeulike.org/user/HEIRS/article/5922922