https://www.mdpi.com/2076-393X/5/4/34/pdf

TLR4 Signaling Pathway Modulators as Potential Therapeutics in Inflammation and Sepsis.

The recognition of invading pathogens and endogenous molecules from damaged tissues by toll-like receptors (TLRs) triggers protective self-defense mechanisms. However, excessive TLR activation disrupts the immune homeostasis by sustained pro-inflammatory cytokines and chemokines production and consequently contributes to the development of many inflammatory and autoimmune diseases, such as systemic lupus erythematosus (SLE), infection-associated sepsis, atherosclerosis and asthma. Therefore, inhibitors/antagonists targeting TLR signals may be beneficial to treat these disorders. In this article, we first briefly summarize the pathophysiological role of TLRs in the inflammatory diseases. We then focus on reviewing the current knowledge in both preclinical and clinical studies of various TLR antagonists/inhibitors for the prevention and treatment of inflammatory diseases. These compounds range from conventional small molecules to therapeutic biologics and nanodevices. In particular, nanodevices are emerging as a new class of potent TLR inhibitors for their unique properties in desired bio-distribution, sustained circulation, and preferred pharmacodynamic and pharmacokinetic profiles. More interestingly, the inhibitory activity of these nanodevices can be regulated through precise nano-functionalization, making them the next generation therapeutics or “nano-drugs”. 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.

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Inhibition of Toll-Like Receptor Signaling as a Promising Therapy for Inflammatory Diseases: A Journey from Molecular to Nano Therapeutics.

Toll-like receptors (TLRs) are an important family of receptors that constitute the first line of defense system against microbes. They can recognize both invading pathogens and endogenous danger molecules released from dying cells and damaged tissues and play a key role in linking innate and adaptive immunity. TLRs are widely distributed in both immune and other body cells. The expressions and locations of TLRs are regulated in response to specific molecules derived from pathogens or damaged host cells. The binding of ligands to TLR activates specific intracellular signaling cascades that initiate host defense reactions. Such binding is ligand-dependent and cell type-dependent and leads to production of pro-inflammatory cytokines and type 1 interferon. TLR-dependent signaling pathways are tightly increased during innate immune responses by a variety of negative regulators. Overactivation of TLRs can ultimately lead to disruption of immune homeostasis and thus increase the risk for inflammatory diseases and autoimmune disorders. Antagonists/inhibitors targeting the TLR signaling pathways have emerged as novel therapeutics to treat these diseases. The present review summarizes the structure, characterizations, and signaling of TLRs and their regulators, as well as describes the implication of TLRs in many diseases with a brief idea about the inhibitors that target TLR signaling pathways. We conclude that TLRs are the main elements of our immune system, and they should be maintained functioning to keep the integrity of innate immunity. Targeting of TLR signaling represents a new challenge for treatment of many diseases.

/pdf/toll-like-receptors-activation-signaling-and-targeting-an-4sv7d34hcw.pdf

Toll-like receptors activation, signaling, and targeting: an overview

Toll-like receptors (TLRs) are germline-encoded receptors that are central to innate and adaptive immune responses. Owing to their vital role in inflammation, TLRs are rational targets in clinics; thus, many ligands and biologics have been reported to overcome the progression of various inflammatory and malignant conditions and support the immune system. For each TLR, at least one, and often many, drug formulations are being evaluated. Ligands reported as stand-alone drugs may also be reported based on their use in combinatorial therapeutics as adjuvants. Despite their profound efficacy in TLR-modulation in preclinical studies, multiple drugs have been terminated at different stages of clinical trials. Here, TLR modulating drugs that have been evaluated in clinical trials are discussed, along with their mode of action, suggestive failure reasons, and ways to improve the clinical outcomes. This review presents recent advances in TLR-targeting drugs and provides directions for more successful immune system manipulation.

https://onlinelibrary.wiley.com/doi/epdf/10.1002/med.21553

Recent clinical trends in Toll‐like receptor targeting therapeutics

Autophagy and inflammasomes.

Introduction 
Toll-like receptors (TLRs) play an important role in the recognition of microbial products and in host defense against infection. However, the massive release of inflammatory mediators into the bloodstream following TLR activation following sepsis is thought to contribute to disease pathogenesis.


Methods 
Here, we evaluated the effects of preventive or therapeutic administration of monoclonal antibodies (mAbs) targeting either TLR2 or TLR4 in a model of severe polymicrobial sepsis induced by cecal ligation and puncture in mice.


Results 
Pre-treatment with anti-TLR2 or anti-TLR4 mAb alone showed significant protection from sepsis-associated death. Protective effects were observed even when the administration of either anti-TLR2 or anti-TLR4 alone was delayed (i.e., 3 h after sepsis induction). Delayed administration of either mAb in combination with antibiotics resulted in additive protection.


Conclusion 
Although attempts to translate preclinical findings to clinical sepsis have failed so far, our preclinical experiments strongly suggest that there is a sufficient therapeutic window within which patients with ongoing sepsis could benefit from combined antibiotic plus anti-TLR2 or anti-TLR4 mAb treatment.

/pdf/therapeutic-effects-of-treatment-with-anti-tlr2-and-anti-584sa9m0gs.pdf

Therapeutic Effects of Treatment with Anti-TLR2 and Anti-TLR4 Monoclonal Antibodies in Polymicrobial Sepsis

This study evaluated the role of macrophage migration inhibitory factor in inflammation caused by monosodium urate crystals. The concentration of macrophage migration inhibitory factor was increased in synovial fluid of patients with acute gout, and there was a positive correlation between intra-articular macrophage migration inhibitory factor and IL-1β concentrations. In mice, the injection of monosodium urate crystals into the knee joint increased the levels of macrophage migration inhibitory factor in macrophages and in inflamed tissue. The injection of recombinant macrophage migration inhibitory factor into the joint of mice reproduced the inflammatory response observed in acute gout, including histologic changes, the recruitment of neutrophils, and increased levels of IL-1β and CXCL1. Importantly, the accumulation of neutrophils and the amount IL-1β in the joints were reduced in macrophage migration inhibitory factor-deficient mice when injected with monosodium urate crystals. We observed a similar effect when we blocked macrophage migration inhibitory factor with (S,R)-3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid or anti-macrophage migration inhibitory factor. In addition, the blockade of IL-1R and CXCR2 reduced recombinant macrophage migration inhibitory factor-induced neutrophil recruitment. Mechanistically, recombinant macrophage migration inhibitory factor is important for the synthesis of il1β mRNA in vivo and in isolated macrophages. Altogether, macrophage migration inhibitory factor promotes neutrophil accumulation and is important for IL-1β production, which are 2 crucial events contributing to the pathogenesis of acute gout.

https://jlb.onlinelibrary.wiley.com/doi/pdf/10.1189/jlb.3MA0915-418R

Irla Paula Stopa Rodrigues

Papers

Therapeutic Effects of Treatment with Anti-TLR2 and Anti-TLR4 Monoclonal Antibodies in Polymicrobial Sepsis

Macrophage migration inhibitory factor drives neutrophil accumulation by facilitating IL-1β production in a murine model of acute gout.