A benzimidazole inhibitor attenuates sterile inflammation induced in a model of systemic autoinflammation in female mice

Abstract

Sterile stimuli can trigger inflammatory responses, and in some cases can lead to a variety of acute or chronic diseases. In this study, we hypothesize that a benzimidazole inhibitor may be used as a therapeutic in the treatment of sterile inflammation. In vitro, this inhibitor blocks TLR signalling and inflammatory responses. The benzimidazole inhibitor does not prevent mouse macrophage activation after stimulation with 2,6,10,14-tetramethylpentadecane (TMPD, also known as pristane), a hydrocarbon oil that mimics features of sterile inflammation when injected in vivo. However, C57BL/6J female mice treated with the benzimidazole inhibitor exhibited a significant reduction of pristane-dependent induction of splenocyte number and weight. Conversely, no significant difference was observed in males. Using mass spectrometry, we found that the urine of pristane-injected mice contained increased levels of putative markers for several inflammatory diseases, which were reduced by the benzimidazole inhibitor. To study the mechanism, we showed that pristane-injected mice had increased cell free DNA in serum, which was not impacted by inhibitor treatment. However, chemokine release (e.g. MCP-1, RANTES and TARC) was significantly reduced in inhibitor-treated mice. Thus, the benzimidazole inhibitor might be used as a new drug to block the recruitment of immune cells during sterile inflammatory diseases in humans. Sterile inflammation is defined as an inflammatory condition triggered by sterile stimuli, such as toxins, minerals and chemicals 1,2 , rather than proinflammatory molecules belonging to pathogenic microbes 3. Similar to pathogen-associated inflammation, sterile inflammation can be initiated by activation of Pattern Recognition Receptors (PRRs), including Toll-like Receptors (TLRs), and leads to production of proinflammatory mediators 1. Furthermore, failure to promptly remove or contain agents causing sterile inflammation can be harmful to the host, leading to chronic inflammation. Nevertheless, it is also possible that sterile inflammation opens space for infection or for the microbiome to exacerbate inflammatory events. Examples of sterile inflammatory disorders are ischemia-reperfusion injury 4 , arteriosclerosis 5 , Alzheimer's disease 6 , and other autoinflammatory and autoimmune diseases 7. Although in the last few years several compounds, such as oridonin 8 and CY-09 9 have been shown to elicit potent therapeutic effects in mouse models of inflammatory diseases; the discovery of new possible anti-inflammatory drugs may lead to the development of more effective therapies towards sterile inflammatory diseases. Here, we used a model of sterile inflammation where the triggering agent is 2,6,10,14-tetramethylpentadecane (TMPD, also known as pristane). Pristane is a naturally occurring hydrocarbon oil found in small quantities in many plants, in various marine organisms, and as the most active component of mineral oil 10. Importantly, there is evidence that properties of certain hydrocarbons such as pristane can med...

Anthelmintic Drugs as Emerging Immune Modulators in Cancer

“…For instance, among the benzimidazole compounds, the molecules N-acyl-2-aminobenzimidazole-1 and -2 were able to block the interleukin-1 receptor-associated kinase (IRAK)-4 function, thus, affecting IL-1 signal transduction [ 39 ]. In vitro studies with bone-marrow-derived macrophages show that N-acyl-2-aminobenzimidazole-1 and -2 inhibit the toll-like receptor (TLR) downstream effectors IRAK1 and IRAK4, leading to a significant reduction in mitogen-activated protein (MAP) kinase phosphorylation, NF-κB nuclear translocation, and subsequent release of cytokines [ 40 ]. In a model of murine sterile inflammation, the compounds reduced splenocyte proliferation, the expression of markers associated with chronic inflammation (e.g., kininogen, kallikrein, and fibronectin), as well as the production of proinflammatory chemokines (e.g., CCL-2, CCL-5, CCL-17), without affecting macrophage activation [ 40 ].…”

“…In vitro studies with bone-marrow-derived macrophages show that N-acyl-2-aminobenzimidazole-1 and -2 inhibit the toll-like receptor (TLR) downstream effectors IRAK1 and IRAK4, leading to a significant reduction in mitogen-activated protein (MAP) kinase phosphorylation, NF-κB nuclear translocation, and subsequent release of cytokines [ 40 ]. In a model of murine sterile inflammation, the compounds reduced splenocyte proliferation, the expression of markers associated with chronic inflammation (e.g., kininogen, kallikrein, and fibronectin), as well as the production of proinflammatory chemokines (e.g., CCL-2, CCL-5, CCL-17), without affecting macrophage activation [ 40 ]. Within the benzimidazole class, albendazole was also reported to exert important immunomodulatory properties in psoriasis [ 41 ], a dermatologic disease associated with an increased risk of developing cancer (i.e., colorectal, skin, gastric, and lung cancer) in selected subgroups of patients [ 53 ].…”

Damage-mediated macrophage polarization in sterile inflammation

“…Sterile inflammation could be induced by overexposure to UVB irradiation (i.e., sunburn) in the mouse plantar skin ( 45 ), polyvinylpyrrolidone (PVP) in rat model ( 46 ), as well as with phorbol 12-myristate 13-acetate (PMA) to induce acute mouse ear inflammation ( 47 ). Another possibility is the stimulation with 2,6,10,14-tetramethylpentadecane (TMPD, also known as pristane) ( 48 ). Additionally, it can be evoked with cytodex bead slurry injection subcutaneously into the back space in mouse ( 49 ), furthermore, the hepatic I/R Injury also can be induced ( 50 ).…”

Crystal Structure, Thermodynamic Properties and DFT Studies of 5,6-dimethyl-1H-benzo[d]imidazol-3-ium 3-((2,4-dioxo-1,5-dioxaspiro[5.5]undecan-3-ylidene)methyl) -2,4-dioxo-1,5-dioxaspiro[5.5]undecane Hydrate

“…Its molecular structure, which includes no H atoms, and its optimized geometric structure are both shown in Figure 1. (10) atom is used to join two 1,5-dioxaspiro [5.5] undecane-2,4-dione moieties. The bond lengths reported for C8-C10 and C10-C11 are 1.389(2) Å and 1.382(2) Å, respectively, which resemble related published compounds (1.386(2) Å, 1.380(2) Å) [24].…”

“…Heterocyclic compounds play an important role in biochemistry, medicinal chemistry, organic chemistry and agrochemical industries. In recent years, attention has been given to the benzimidazole class of compounds due to their diverse biological activities, such as anticancer [1,2], antifungal [3], antioxidant [4], cytotoxic [5], antiprotozoal [6], anti-T. cruzi (Trypanosoma cruzi) [7], antiproliferative [8], antihistaminic [9], anti-inflammatory [10], analgesics [11], antibacterial [12], anticonvulsant [13] and acetylcholinesterase [14]. In addition, benzimidazole has been used as corrosion inhibition for mild steel [15], catalytic activity [16], fluorescence chemosensors [17] and chiroptical sensors [18].…”