Editorial

Toll-Like Receptors as a Therapeutic Target From Past to Future

Introduction

In the context of human and mammalian immunology, Toll-like receptors (TLRs) as an innate immune receptor were first distinguished on human macrophages in 1997. TLR expression was found to be expressed by cells of adaptive immunity such as T cells in addition to innate immune cells in subsequent immunology studies.¹ In addition to having a direct impact on the biology of the innate immune response, B cells and TLRs have been shown to affect the development, activation, survival, and associated immune response of various types of T cells and B cells.² TLRs, on the other hand, were found to be expressed by newly discovered cells known as innate lymphoid cells (ILCs), which resemble lymphoid cells but are actually a different form of hematopoietic innate immune cells.^3-5 These ILCs, for instance, express some of the TLRs such as TLR2 and TLR3, but they do not express TLR4 or TLR7.^6-8 In addition, a specific population of ILCs known as c-Kit + which was found to expand in humans during filarial worm or helminthic infection expresses TLR5, TLR7, and TLR9. In response to the TLR6 ligand, these purified c-Kit + ILCs produce a greater amount of granulocyte-macrophage colony-stimulating factor. However, no additional prototypic cytokines such as IL-5, IL-17A, or interferon-γ were produced by TLR-signaling in the c-Kit + ILCs. Nevertheless, cytokine production from human type 3 ILCs is only triggered by TLR2 agonists when IL-2, IL-15, and IL-23 are present.^9-11 In simian immunodeficiency virus-infected macaques, this specific expression of TLR2 on type 3 ILCs or lymphoid tissue inducer cells is responsible for inducing the apoptosis of these cells. Cancer and autoimmunity are two examples of sterile inflammatory conditions in which TLRs play a significant role. For instance, they have been ensnared in the pathogenesis of a few auto-safe sicknesses, including systemic lupus erythematosus, rheumatoid arthritis, seronegative spondyloarthritides, multiple sclerosis, experimental autoimmune encephalomyelitis, type 2 diabetes mellitus, foundational sclerosis, Sjogren’s syndrome, and myositis (a persistent provocative immune system illness principally influencing skeletal muscles, causing serious muscle shortcoming and weariness). They have additionally been related to the pathogenesis of a few human diseases, including B cell malignancies, colorectal disease, basal cell carcinoma, bladder malignant growth, and different tumors.¹² New immunotherapies for autoimmune and cancer diseases have been developed as a result of TLRs’ involvement in their pathogenesis. To improve the effectiveness of radiation therapy in halting tumor growth, even TLR-mediated immune stimulation is being utilized. For instance, a number of TLRs have recently been linked to the pathogenesis of neurodegenerative conditions as well as the mechanisms by which these conditions can be repaired.^13-15 As a result, therapeutic approaches to infectious and non-infectious diseases target TLRs because of their significant role. Even some studies have demonstrated that these TLRs can regulate the processes of steroidogenesis and spermatogenesis in males and ovulation, fertilization, gestation, and parturition in females, respectively, to control reproduction in mammals. Regeneration (e.g., liver regeneration in mammals) has also been linked to TLRs. Acute and chronic rejection of organ transplants is also facilitated by their involvement in allograft inflammation. TLRs have been discovered in humans for 20 years, and their roles in infections, inflammation, reproduction, development, autoimmunity, cancer, allograft inflammation/rejection, and regeneration are now ruling human biology.^16-18 Nevertheless, the unexplored role of TLR in extremely complex mammalian/human biology can be explored through ongoing research in the field of TLRs. TLRs are amazing, but their evolution and the mammals’ biology under homeostatic and inflammatory disease conditions need further study.¹⁹ As a result, a variety of TLR agonists and antagonists have been developed to target a variety of inflammatory conditions, including cancer and autoimmunity, in addition to controlling various biological functions.²⁰

Acknowledgements

I would like to appreciate the cooperation of Jiangsu University, Department of Immunology stuff.

Competing Interests

The author declares that he has no competing interests.

Consent for Publication

Not applicable.

Ethical Approval

Not applicable.

Funding

Not applicable.

References

1. Schmulson M. Síndrome de intestino irritable. In: Schmulson M, ed. Clínicas de Gastroenterología de México, Motilidad y Trastornos Funcionales Digestivos. Asociación Mexicana de Gastroenterología. 1st ed. Vol 1. Mexico, DF: Editorial Alfil SA de CV; 2008. p. 109-28.
2. Cash BD, Schoenfeld P, Chey WD. The utility of diagnostic tests in irritable bowel syndrome patients: a systematic review. Am J Gastroenterol 2002; 97(11):2812-9. doi: 10.1111/j.1572-0241.2002.07027.x [Crossref] [ Google Scholar]
3. Lopez-Colombo A, Bravo-Gonzales D, Corona-Lopez A, Perez-Lopez ME, Cervantes-Ocampo M, Romero-Ogawa T. First community-based study of functional gastrointestinal disorders (FGID) in México using the Rome II modular questionnaire. Gastroenterology 2006; 130(Suppl 2):A508. [ Google Scholar]
4. Schmulson M, Ortíz O, Santiago-Lomeli M, Gutiérrez-Reyes G, Gutiérrez-Ruiz MC, Robles-Díaz G. Frequency of functional bowel disorders among healthy volunteers in Mexico City. Dig Dis 2006; 24(3-4):342-7. doi: 10.1159/000092887 [Crossref] [ Google Scholar]
5. Schmulson M, Adeyemo M, Gutiérrez-Reyes G, Charúa-Guindic L, Farfán-Labonne B, Ostrosky-Solis F. Differences in gastrointestinal symptoms according to gender in Rome II positive IBS and dyspepsia in a Latin American population. Am J Gastroenterol 2010; 105(4):925-32. doi: 10.1038/ajg.2010.58 [Crossref] [ Google Scholar]
6. Gwee KA. Post-infectious irritable bowel syndrome, an inflammation-immunological model with relevance for other IBS and functional dyspepsia. J Neurogastroenterol Motil 2010; 16(1):30-4. doi: 10.5056/jnm.2010.16.1.30 [Crossref] [ Google Scholar]
7. Quigley EM. Irritable bowel syndrome and inflammatory bowel disease: interrelated diseases?. Chin J Dig Dis 2005; 6(3):122-32. doi: 10.1111/j.1443-9573.2005.00202.x [Crossref] [ Google Scholar]
8. Bercik P, Verdu EF, Collins SM. Is irritable bowel syndrome a low-grade inflammatory bowel disease?. Gastroenterol Clin North Am 2005; 34(2):235-45. doi: 10.1016/j.gtc.2005.02.007 [Crossref] [ Google Scholar]
9. Kumar V, Ahmad A. Role of MAIT cells in the immunopathogenesis of inflammatory diseases: new players in old game. Int Rev Immunol 2018; 37(2):90-110. doi: 10.1080/08830185.2017.1380199 [Crossref] [ Google Scholar]
10. Morgan BP, Harris CL. Complement, a target for therapy in inflammatory and degenerative diseases. Nat Rev Drug Discov 2015; 14(12):857-77. doi: 10.1038/nrd4657 [Crossref] [ Google Scholar]
11. Pasupuleti M, Schmidtchen A, Malmsten M. Antimicrobial peptides: key components of the innate immune system. Crit Rev Biotechnol 2012; 32(2):143-71. doi: 10.3109/07388551.2011.594423 [Crossref] [ Google Scholar]
12. Wiesner J, Vilcinskas A. Antimicrobial peptides: the ancient arm of the human immune system. Virulence 2010; 1(5):440-64. doi: 10.4161/viru.1.5.12983 [Crossref] [ Google Scholar]
13. Diamond G, Beckloff N, Weinberg A, Kisich KO. The roles of antimicrobial peptides in innate host defense. Curr Pharm Des 2009; 15(21):2377-92. doi: 10.2174/138161209788682325 [Crossref] [ Google Scholar]
14. Malinen E, Rinttilä T, Kajander K, Mättö J, Kassinen A, Krogius L. Analysis of the fecal microbiota of irritable bowel syndrome patients and healthy controls with real-time PCR. Am J Gastroenterol 2005; 100(2):373-82. doi: 10.1111/j.1572-0241.2005.40312.x [Crossref] [ Google Scholar]
15. Kassinen A, Krogius-Kurikka L, Mäkivuokko H, Rinttilä T, Paulin L, Corander J. The fecal microbiota of irritable bowel syndrome patients differs significantly from that of healthy subjects. Gastroenterology 2007; 133(1):24-33. doi: 10.1053/j.gastro.2007.04.005 [Crossref] [ Google Scholar]
16. Saito YA, Zimmerman JM, Harmsen WS, De Andrade M, Locke GR 3rd, Petersen GM. Irritable bowel syndrome aggregates strongly in families: a family-based case-control study. Neurogastroenterol Motil 2008; 20(7):790-7. doi: 10.1111/j.1365-2982.2007.1077.x [Crossref] [ Google Scholar]
17. Bengtson MB, Rønning T, Vatn MH, Harris JR. Irritable bowel syndrome in twins: genes and environment. Gut 2006; 55(12):1754-9. doi: 10.1136/gut.2006.097287 [Crossref] [ Google Scholar]
18. Camilleri M. Genetics and irritable bowel syndrome: from genomics to intermediate phenotype and pharmacogenetics. Dig Dis Sci 2009; 54(11):2318-24. doi: 10.1007/s10620-009-0903-4 [Crossref] [ Google Scholar]
19. Gonsalkorale WM, Perrey C, Pravica V, Whorwell PJ, Hutchinson IV. Interleukin 10 genotypes in irritable bowel syndrome: evidence for an inflammatory component?. Gut 2003; 52(1):91-3. doi: 10.1136/gut.52.1.91 [Crossref] [ Google Scholar]
20. van der Veek PP, van den Berg M, de Kroon YE, Verspaget HW, Masclee AA. Role of tumor necrosis factor-alpha and interleukin-10 gene polymorphisms in irritable bowel syndrome. Am J Gastroenterol 2005; 100(11):2510-6. doi: 10.1111/j.1572-0241.2005.00257.x [Crossref] [ Google Scholar]