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. compounds range from standard small molecules to therapeutic biologics and nanodevices. In particular, nanodevices are emerging as a new class of potent TLR inhibitors for FD-IN-1 their unique properties in desired bio-distribution, sustained blood circulation, and favored 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 spotlight the pharmacological regulation of TLR signaling, especially on multiple TLR pathways, as future encouraging therapeutic strategy for numerous inflammatory and autoimmune diseases. tracking (bioimaging). Accordingly, novel nanodevices have emerged with bio-activities to potently Rabbit Polyclonal to KCNMB2 regulate TLR signaling, aiming for inhibiting disease-associated TLR activation. In this review, we first briefly summarize the pathophysiological role of TLRs in many diseases of acute and chronic inflammation as well as autoimmunity. These diseases include SLE in autoimmunity, infection-induced sepsis for acute inflammation, vascular system disorders across both acute and chronic inflammation, and other inflammation-associated diseases such as psoriasis, gastrointestinal cancer, asthma, and chronic obstructive pulmonary disease (COPD; Table ?Table1).1). We then focus on the current knowledge in developing TLR antagonists and inhibitors at various stages from pre-clinical evaluation to clinical trials, including the most recent development of nano-based modulators on inhibition of TLR signaling, and discuss their potential uses in FD-IN-1 treating various inflammatory diseases. Particularly, we describe the design of these nanodevices and discuss their mechanism(s) of action in TLR inhibition. Due to the unique feature of nanodevices, these nano-inhibitors hold great promises in treating various inflammatory and autoimmune diseases. Table 1 The role of TLR activation in the pathogenesis of inflammatory diseases. infection and severe colitis of patients with inflammatory bowel diseases (IBD) greatly increase the risk of having gastrointestinal malignancies (Itzkowitz and Yio, 2004; Houghton and Wang, 2005), and TLR signaling is evidently involved in such inflammatory complications (Fukata and Abreu, 2008). It has been found that TLR4/MyD88 pathway can promote the development of colitis-associated colorectal tumors (Fukata et al., 2007). Since tumor cells also express TLR4, TLR4-induced uncontrolled production of immunosuppressive cytokines has been suggested to contribute to the tumor progression (Sato et al., 2009). In inflammatory airway diseases, such as asthma and COPD, TLR signaling pathways are closely linked to the disease pathophysiology (Bezemer et al., 2012). For examples, house dust mites, one of the main risk factors for allergic asthma has been suggested to trigger airway neutrophils and monocytes through a TLR4-dependent mechanism (Li et al., 2010). Furthermore, the TLR4 agonist LPS is able to induce either Th1 or Th2 immune response in asthma in a dose dependent manner (Dong et al., 2009). In the case of COPD, TLR2, TLR4, and TLR9 have been shown to participate in cigarette smoke-induced inflammatory responses (Droemann et al., 2005; Karimi et al., 2006; Mortaz et al., 2010). During the exacerbation of the airway diseases, overactive TLR signaling can contribute to excessive inflammatory responses and lung tissue destruction (Tokairin et al., 2008; Stowell et al., 2009). Toll-like receptor antagonists/inhibitors and their clinical applications Although, evolutionarily TLRs are essential elements in innate immune system and play a critical role in the host defensive mechanism against invading pathogens, overactivation of TLRs is inevitably involved in the pathogenesis of many inflammatory FD-IN-1 diseases. Thus, inhibition of TLR signaling pathways has been predicted to be an effective therapeutic strategy to suppress unwanted, disease-associated inflammatory responses. In general, TLR inhibition can be achieved by two major strategies: (1) blocking the binding of TLR ligands to the receptor; (2) interfering the intracellular signaling pathways to stop the signal transduction (Figure ?(Figure2).2). Accordingly, various therapeutic agents for inhibiting TLR signaling have been developed to control excessive inflammation; they can be classified as small molecule inhibitors, antibodies, oligonucleotides, lipid-A analogs, microRNAs, and new emerging nano-inhibitors. The current FD-IN-1 advances of each class are summarized and discussed hereafter (Tables ?(Tables22C5). Open in a separate window Figure 2 Potential drug targets of TLR signaling pathways. The TLR inhibition can be achieved through two major strategies: (1) blocking the binding of the agonists to the corresponding TLRs, and (2) inhibiting the intracellular signaling of the TLR pathways. The antibodies, lipid A analogs and oligonucleotides primarily target at the.