TLRs are among the most well-studied and well-characterized pattern recognition receptors (PRRs), due to their ability to detect a variety of pathogenassociated molecular patterns (PAMPs), such as lipids, proteins, lipoproteins, and nucleic acids. To date, 10 human TLRs have been identified, and each TLR has a specific set of ligands that it can detect. TLR4 recognizes the lipopolysaccharide (LPS) of Gram-negative bacteria. TLR2 can heterodimerize with TLR1 or TLR6, and recognize peptidoglycan, lipopeptide, and lipoproteins. TLR3 recognizes double-stranded RNA (dsRNA). TLR5 has been shown to recognize bacterial flagellin. TLR7 and TLR8 can recognize imidazoquinolines and single-stranded RNA. TLR9 recognizes bacterial and viral CpG DNA motifs and the malaria pigment hemozoin. Although the ligand for TLR10 is currently unknown, it has been demonstrated that TLR10 can heterodimerize with TLR1 or TLR2. Whereas all TLRs can mediate the production of inflammatory cytokines, activation of TLR3, TLR4, TLR7, TLR8, and TLR9 can result in the production of type I IFNs that are important for antiviral immune responses. 
After recognizing PAMPs, TLRs activate intracellular signaling pathways that lead to the induction of inflammatory cytokine genes such as TNF, IL-6, IL-1 and IL-12. MyD88 is a universal adapter that activates inflammatory pathways; it is shared by all TLRs with the exception of TLR3. Recruitment of MyD88 leads to the activation of MAP kinases (MAPKs) (ERK, JNK, p38) and the transcription factor NF- B to control the expression of inflammatory cytokine genes. TIRAP mediates the activation of a MyD88-dependent pathway downstream of TLR2 and TLR4. TRIF is recruited to TLR3 and TLR4, and activates an alternative pathway (TRIF-dependent pathway) that culminates in the activation of NF- B, MAPKs and the transcription factor IRF3. Activation of IRF3 is pivotal for induction of type I IFN, particularly IFN. TRAM selectively participates in the activation of the TRIF-dependent pathway downstream of TLR4, but not TLR3.


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