Effects of LDN:
•
blocks TLR-4 on microglia (anti-inflammatory)
That's not 100% positive effect because of:
Inhibition of Toll-Like Receptor Signaling as a Promising Therapy for Inflammatory Diseases: A Journey from Molecular to Nano Therapeutics
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5516312/
Although, significant efforts have been made in developing different kinds of new
TLR inhibitors/antagonists, only limited numbers of them have undergone clinical trials, and none have been approved for clinical uses to date. Nevertheless, these findings and continuous studies of
TLR inhibition highlight the pharmacological regulation of
TLR signaling, especially on multiple
TLR pathways, as future promising therapeutic strategy for various inflammatory and autoimmune diseases.
...
Due to their capability of recognizing a variety of PAMPs, TLRs play a critical role in fighting against pathogen infection (Mogensen, 2009). The first identified TLR4 can detect a wide range of Gram-negative bacteria by recognizing and responding to the coating molecules on the bacteria cell wall—lipopolysaccharide (LPS). TLR2 (in conjunction with either TLR1 or TLR6) primarily recognizes lipoproteins/lipopeptides and glycolipids from various pathogens including microbes and fungi. TLR5 is the only
TLR that identifies a protein ligand—flagellin from nearly all flagellated bacteria. On the other hand, the endosomal TLRs (TLR3, and TLR7-TLR9) are mainly responsible for the recognition of nucleic acid ligands, including dsRNA, ssRNA, and CpG-DNA, from viral and intracellular bacterial infection. Therefore, activation of TLRs by engaging with these PAMPs allows the host to combat invading pathogens.
In fact, TLR agonists have long been considered as vaccine adjuvants to boost the immune system to eliminate viral infections and most recently fight cancer (O'Neill et al., 2009; Hedayat et al., 2011).
...
The expression of TLRs can be found in a variety of immune cells (e.g., dendritic cells, monocytes, macrophages, and B lymphocytes) and non-immune cells (e.g., epithelial cells, endothelial cells, and fibroblasts; Takeda et al., 2003).
The development status of
TLR antagonists/inhibitors: class of SMIs:
Valsartan ARB, TLR4
Animal study Novartis Pharma Yang et al., 2009
Usefulness of oral administration of lipopolysaccharide for disease prevention through the induction of priming in macrophages
http://ar.iiarjournals.org/content/34/8/4497.long
Coley's toxin has been used as an immunotherapy in patients with cancer since 1891, and this practice is continued even today because of positive experience gained from more than 120 yearsn of use. Coley's toxin contains a mixture of dead Serratia marcescens and Streptococcus pyogenes bacteria and is known as a LPS-containing therapeutic agent (17).
...
Considering the purposiveness of the LPS, we believe that LPS may be regarded as a micronutrient with some medicinal properties for the human body rather than as an endotoxin. For example, epidemiological studies show that LPS is inversely correlated with risk of allergic disease (hygiene hypothesis) (23). The knockout of the gene of the LPS receptor in mice results in low resistance to infection (24). Moreover, the amount of LPS in various foods indicates that some herbal Chinese medicines contain a few tens of micrograms of LPS per gram of dry weight (8), whereas health foods contain several micrograms. These data suggest that ingestion of a certain amount of LPS may be important for health maintenance.
...
We have studied the preventative and curative effects on various diseases of oral administration of Pantoea agglomerans LPS, originally isolated from wheat flour. We observed several effects, such as protection from infectious diseases [bacterial and parasitic (toxoplasmosis)], improvement of diabetes and lipid metabolism (14), antiallergic properties in atopic dermatitis (13), an infection prophylaxis effect (25), and beneficial effects in cancer (26). LPS performs an important function in regulation of intestinal bacterial flora through the induction of bactericidal peptides (27). After oral administration, LPS is delivered to Paneth cells in intestinal crypts and induces production of bactericidal peptides defensins, such as regenerating islet-derived protein 3 gamma (28) and cryptdin-4 (29). According to the report of Masuda et al., cryptdin-4 has the ability to control the growth of pathogenic bacteria in the intestine (29).
...
In a model of chronic stress based on daily dexamethasone injection in chicken, antibody production against a Salmonella vaccine was significantly decreased. Oral administration of P. agglomerans LPS improved the antibody titer against Salmonella in this chronic stress model (31). It was also shown that oral administration of LPS protects against steroidal withering of immune system organs: the spleen and bursa. These results indicate that oral administration of LPS saves immune cells from death caused by several types of stress.
Next Section
Conclusion – Macrophages and LPS for Maintaining Health
Macrophages recognize and eliminate oxidized lipids, denatured proteins, advanced glycation end-products, and dead cells. These are the true causative agents of chronic inflammation, which can lead to several diseases such as diabetes, arteriosclerosis, cancer, allergy, and dementia. As mentioned above, the essential role of macrophages in health maintenance is mainly believed to be the removal of waste products from the body. In accordance with this concept, we believe that a new paradigm should be adopted for health maintenance. For example, an outbreak of a disease may be the result of suppression of macrophage function that ensures elimination of waste products.
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P.S. Lipopolysaccharide(LPS) is a TLR4 agonist:
https://www.invivogen.com/review-lps-tlr4
