Toll gates: An emerging therapeutic target

Abstract

Innate immune system forms the first line of defense against microbial infections, as it exerts an immediate response. Innate immunity works through Toll-like receptors (TLRs) which functions as primary sensors of pathogens. TLR activates multiple signaling cascades leading to the induction of genes responsible for the release of inflammatory cytokines and type I interferon. Thus, they induce antimicrobial responses and also have an instructive role in adaptive immunity. However, TLR-mediated inflammation is said to be responsible for many of the destructive host responses in inflammatory diseases like periodontitis. Hence, therapeutics targeting TLRs are being used to treat disease such as HIV, Hepatitis B, asthma etc. Recently, synthetic TLR agonists are tried as novel vaccine adjuvant in treating periodontal diseases. This paper reviews the scope of TLR-based therapeutics in treating periodontitis.

The Alpha-Melanocyte-Stimulating Hormone Suppresses TLR2-Mediated Functional Responses through IRAK-M in Normal Human Keratinocytes

“…The activation of TLR signaling pathways induced by specific pathogens ultimately results in NF-κB transactivation, followed by secreting inflammatory cytokines such as IL-1, IL-6, TNFα and IL-8, by which innate inflammatory immune responses are initiated. NF-κB signaling activation associated with TLRs is thought to be a pivotal link between the innate and adaptive immune systems since TLRs not only provoke the innate immune response and enhance adaptive immunity against pathogens, but also are involved in the pathogenesis of autoimmune and chronic inflammation [ 32 ]. It was previously reported that the treatment of LPS-stimulated macrophages with α-MSH inhibits the NF-κB nuclear translocation and p38 activation by blocking TLR4 signaling using the intracellular TLR-inhibitor IRAK-M [ 31 , 33 , 34 ].…”

Innate Immune Response as a New Challenge in Periodontal Inflammation

“…• TLR antagonists. [102] Despite the potential of TLRs to activate the synthesis of protective molecules against infection, they can also induce serious immunopathological reactions in case of overstimulation or insufficient control due to the limited action of some negative regulators. An increased number of negative regulators able to dampen the degree and duration of TLR-mediated inflammatory host response were proposed.…”

Combination antiretroviral therapy (cART) restores HIV-1 infection-mediated impairment of JAK-STAT signaling pathway

“…The innate immune system includes three classes of receptors, Toll-like receptors (TLRs), retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs), and nucleotide oligomerization domain (NOD)-like receptors (NLRs) [ 2 ]. Among these receptors, TLRs function as the primary sensors of pathogens, activation of which can stimulate several signaling pathways [ 3 ], including the Janus kinase–signal transducer and activator of transcription (JAK-STAT).…”

“…The IFN-stimulated gene factor 3 (ISGF3), formed by STAT1, STAT2, and interferon regulatory factor (IRF)-9, is a pivotal transcription factor in the JAK-STAT pathway [ 4 – 6 ]. The production of IFNs in cells is in response to the infection by a variety of viruses [ 6 ], which mainly recognized the presence of the viral genome or viral proteins by TLRs [ 3 , 7 – 9 ]. There are 13 TLRs identified in mice and 11 in humans, of which TLR-3, −7, −8, and −9 can detect viral or bacterial nucleic acids [ 3 ], and TLR-1 and 6 can recognize some viral proteins [ 10 ].…”

“…The production of IFNs in cells is in response to the infection by a variety of viruses [ 6 ], which mainly recognized the presence of the viral genome or viral proteins by TLRs [ 3 , 7 – 9 ]. There are 13 TLRs identified in mice and 11 in humans, of which TLR-3, −7, −8, and −9 can detect viral or bacterial nucleic acids [ 3 ], and TLR-1 and 6 can recognize some viral proteins [ 10 ]. All TLRs except TLR-3 have been found to be able to activate a common signaling pathway leading to the production of the proinflammatory cytokines via myeloid differentiation factor 88 (MyD88) [ 2 ].…”