Dear Colleagues,

Toll-like receptors (TLRs) are members of the pattern-recognition receptor (PRR) family that play a central role in the initiation of innate cellular immune responses and the subsequent adaptive immune responses to microbial pathogens. They receive their importance from their ability to recognize microbe-specific molecular signatures from invading pathogens (PAMP, Pathogen Associated Molecular Patterns) as well as self-derived molecules from damaged cells (DAMP, Damage-associated molecular patterns) to trigger the process of self-healing and tissue repair. TLRs are expressed in innate immune cells such as dendritic cells (DCs) and macrophages along with non-immune cells such as fibroblasts and epithelial cells. 
They play a key role in linking innate and adaptive immunity along with being involved in the maintenance of tissue homeostasis by regulating tissue repair and regeneration. 
Previously, several studies have presented considerable evidence that excessive or aberrant TLR activation by PAMPs, mutations of TLR signaling molecules, and DAMPs-mediated TLRs signaling activation could disrupt the immune homeostasis by sustained pro-inflammatory cytokines and chemokine production, thus contributing to the development and progression of numerous diseases. For example, TLR signaling dysregulation contributes to the development and progression of autoimmune diseases including lupus erythematous and rheumatoid arthritis. Upregulation of some TLRs has been shown in various tumor cells, tissues, and tumor cell lines. Excessive TLR activation can lead to systemic inflammation, characterized as sepsis, and can contribute to the development and progression of atherosclerosis, cardiac dysfunction, and congestive heart failure. Also, diseases such as Alzheimer’s disease and type 1 diabetes are linked to TLR dysregulation. 
Growing evidence has emerged suggesting that the inhibition of TLR signaling pathways could be an effective therapeutic strategy to suppress unwanted, disease-associated inflammatory responses. 
Clinical trials are suggesting various therapeutic agents for inhibiting TLR signaling to control excessive inflammation; they can be classified as small molecule inhibitors, antibodies, oligonucleotides, lipid-A analogs, microRNAs, and new emerging nano-inhibitors. 
A deeper progression in our understanding of the TLR signaling pathway and regulation can allow us to manipulate them in specific strategies to treat various diseases that are intimately linked with innate immune signaling. 

Dr.  Francesca Arnaboldi
Guest Editor