A link between gene polymorphism and molecular risk for diabetes foot (DF) disease in patients with T2DM is also observed [419]. It is impossible to include all TLR (TLR1-TLR10) SNPs in humans and their association with the disease susceptibility here in this manuscript, therefore, this information can be found in detail in references mentioned [398,[420], [421], [422]]. therapeutic drug development for various infectious and inflammatory diseases including cancer. Even, Single nucleotide polymorphisms (SNPs) among various TLR genes have been identified among the different human population and their association with susceptibility/resistance to certain infections and other inflammatory diseases. Thus, in the present review the current and future importance of 20-HETE TLRs in immunity, their pattern of expression among various immune cells along with TLR based therapeutic approach is usually reviewed. (([26] and then subsequent recognition of its one homolog called TLR4 in humans in 1997 [27] revolutionized the field of innate immunity. This novel discovery of TLR4 in humans filled the great gap stayed long in the field of immunology that is how pathogens and microbes are recognized by host immune system. However, a variation in TLR4 expression and function in different animal species is also observed [28]. In addition to the variation in expression of TLR4 among different animals, a great variation in expression of the number of 20-HETE TLRs in the animal kingdom is usually observed [29]. For example, Purple sea urchin or expresses most that is 222 TLRs, Amphioxus or expresses 42 TLRs, Xenopus or expresses 19 TLRs, while Zebra fish or expresses 17 TLRs [30,31]. This can be explained on the basis of the evolutionary primitiveness of the animal. This is because TLRs are involved in the recognition of almost every pathogen including bacteria, viruses, fungi, and parasites in animals as soon as they come in contact with the host via any route of pathogen exposure [[32], [33], [34]]. Thus, TLRs are very important PRRs of immune system required to initiate an effective innate immune response at an early stage of contamination [35,36]. While at later stages these TLRs regulate the generation of adaptive immune response [[37], [38], [39]]. Thus, TLRs are still sitting over the top of the immune system pyramid since their first discovery in in 1988 and will they be remain sitting at this position in the ever-changing and evolving field of innate immunity and immunology. This review is designed to highlight the past, present, and future of TLRs in immunity in terms of their pattern of expression in various immune cells, recognition of various TLR SNPs in humans making them resistant/susceptible to various infections and inflammatory disease and development of various TLR agonists and antagonist as pharmacological therapeutics and/or vaccine adjuvants. 2.?Recognition of pathogens by TLRs and generation of inflammatory immune response 2.1. Discovery of TLRs and their recognition as PRRs The Toll protein was first identified in or common fruit fly as an integral membrane protein with a cytoplasmic domain name and a large extra cytoplasmic domain name with a role in dorso-ventral body patterning during embryonic development as a maternal effect gene [26]. The further study established that maternal expression of genes plays an important role in the correct spatial organization of lateral and ventral structures of Drosophila embryo [40]. While expression of gene in the embryo is an essential factor for the survival of embryo and this zygotic Toll protein exhibits comparable biochemical activity as shown by maternal Toll protein [40]. Thus, Toll proteins were first identified as very important proteins responsible for the viability of the insect embryo and their development along with patterning. In 1991, Gay and 20-HETE Keith showed that cytoplasmic domain name of Toll protein of was related to interleukin-1receptor (IL-1R) of humans [41]. These Toll proteins were further shown to exert antifungal action in via regulating the gene responsible for synthesis of an antifungal peptide called drosomycin [42]. Thus, an era of recognition of TLRs as PRRs was about to begin as Smcb later in 1997 human homolog of Toll protein.