Biology:Thymic stromal lymphopoietin

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Short description: Cytokine, alarmin, and growth factor.

Thymic stromal lymphopoietin (TSLP) is an interleukin (IL)-2-like cytokine, alarmin, and growth factor involved in numerous physiological and pathological processes, primarily those of the immune system.[1][2] It shares a common ancestor with IL-7.[3]

A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

Originally appreciated for its role in immune cell proliferation and development, and then for its pivotal role in type 2 immune responses, TSLP is now known to be involved in other types of immune responses, autoimmune disease, and certain cancers.[1][2][4]

Gene ontology

TSLP production has been observed in numerous species, including humans and mice.

In humans, TSLP is encoded by the TSLP gene.[5][6] Alternative splicing of TSLP results in two transcript variants, a long form (lfTSLP, or just TSLP[1]) consisting of 159 amino acid residues, and a short form (sfTSLP) consisting of 63 amino acid residues. These variants use different initiation methionine codons and share a carboxy terminus.[6][7]

sfTSLP

sfTSLP mRNA is constitutively expressed in normal human bronchial epithelial cells (NHBE), normal human lung fibroblasts (NHLF), and bronchial smooth muscle cells (BSMC).[7] sfTSLP mRNA expression is not significantly upregulated by inflammation.[1]

TSLP

TSLP mRNA is not constitutively expressed in NHBE and has a low level of constitutive expression in NHLF and BSMC. TSLP mRNA expression is upregulated by certain Toll-like receptor (TLR) ligands such as flagellin and poly(I:C), but not by lipopolysaccharide (LPS) or macrophage-activating lipopeptide 2 (MALP-2).[7]

Discovery

As the name suggests, TSLP was initially discovered as a growth factor derived from the supernatant of a mouse thymic stromal cell line that was found to promote the survival and proliferation of B lymphocytes.[8]

Function

TSLP was initially observed to have both pro-inflammatory and anti-inflammatory activity. It is now clear that this seemingly ambivalent action can actually be divided between the two transcript variants, with TSLP being pro-inflammatory and sfTSLP being anti-inflammatory.[1][9]

sfTSLP

sfTSLP inhalation prevents airway epithelial barrier disruption caused by the inhalation of house dust mite (HDM) antigens in mice who had been sensitised to HDM, an asthma-like model.[10] Similarly, sfTSLP reduces the severity of dextran sulphate sodium (DSS)-induced colitis in mice, a model of inflammatory bowel disease (IBD), and prevents endotoxic shock and sepsis resulting from bacterial infections.[9]

Signalling

A receptor for sfTSLP has not been discovered. It is not known whether sfTSLP also signals via the TSLP receptor complex.[11]

TSLP

Epithelium defense

TSLP's pivotal role in initiating immune responses begins with its release by epithelial or stromal cells of the lungs, skin, or gastrointestinal tract as an alarmin following mechanical cell injury, pattern recognition receptor (PRR) and protease-activated receptor (PAR) activation, stimulation by certain cytokines, chemical irritation, or infection.[1]

When local mast cells bind an allergen, they produce TSLP indirectly by releasing tryptase in an FcεRI-dependent manner, activating PARs on epithelial cells and causing them to release TSLP.[12] Unlike IL-33, a similarly acting alarmin, TSLP is usually not constitutively expressed and must be upregulated by transcription factors such as nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) or activator protein (AP)1 following insult.[1][13]

Type 2 immune responses

Local dendritic cells (DCs) are among the most important targets of TSPL, as they, among other antigen presenting cells (APCs), allow the immune system to mount adaptive responses. TSLP signalling grants DCs the exact phenotype needed to prime naive CD4+ T cells into TH2 pro-inflammatory cells, or producing type 2 cytokines, namely by upregulating OX40L, CD80, and CD86. TSLP-stimulated DCs that migrate into draining lymph nodes can prime CD4+ T cells into follicular helper T (TFH) cells, which in turn can promote immunoglobulin (Ig)G and E production by resident B lymphocytes, thus initiating type 2 immune responses. TH2 can also facilitate B cell class switching towards IgE.[14]

Type 1 and 3 immune responses

As mentioned, TSLP serves as an alarmin following TLR binding by certain pathogen-associated molecular patterns (PAMPs), including viral and bacterial ones, rather than just irritation by allergens. Thus, TSLP also plays an early role in the initiation of type 1 and 3 immune responses to pathogens. This activity has thus far been best described in the respiratory mucosa.[15]

TSLP-activated CD11b+ DCs can promote the proliferation and long-term survival of CD8+ cytotoxic T cells, promoting the development of lasting adaptive cellular immunity. Analogously, TSLP-activated CD11c+ cells are essential for the development of IgA antibodies following pneumococcal infection. TSLP also holds considerable promise as a novel vaccine adjuvant and anti-cancer immunotherapy due to its broad and potent alarmin functionality, as is evidenced by numerous animal studies.[15]

Germinal centre formation

Germinal centres (GCs) are microstructures that form in secondary lymphoid organs during immune responses. GCs are the sites of the clonal expansion of B lymphocytes and the affinity maturation of their antibodies, thus allowing the immune system to generate antibodies with a high affinity for antigens.[16] TSLP may play an important role in the formation of GCs, as the depletion of TSPLR in CD4+ T cells prevented their formation in mice, as well as the generation of IgG1.[17]

Signalling

Crystal structure of human TSLP in complex with TSLP-R and IL-7Ra (pdb 5j11)[18]

TSLP signals through a heterodimeric receptor complex composed of the TSLP receptor (TSLPR) and the IL-7Rα chain. Upon binding, Janus kinase (JAK)1 and 2 are activated, leading to the activation of signal transducer and activator of transcription (STAT)5A and 5B and, to a lesser extent, STAT1 and 3. These transcription factors upregulate pro-inflammatory cytokines such as IL-4, 5, 9, and 13.[1][19]

Disease

TSLP expression is linked to many disease states including asthma,[20] inflammatory arthritis,[21] atopic dermatitis,[22] eczema, eosinophilic esophagitis and other allergic states.[23][24] The factors inducing the activation of TSLP release are not clearly defined.

Asthma

Expression of TSLP is enhanced under asthma-like conditions (aka Airway HyperResponsiveness or AHR model in the mouse), conditioning APCs in order to orient the differentiation of T cells coming into the lungs towards a TH2 profile (T helper 2 pathway).[citation needed] The TH2 cells then release factors promoting an inflammatory reaction following the repeated contact with a specific antigen in the airways.[citation needed]

Atopic dermatitis

TSLP-activated Langerhans cells of the epidermis induce the production of pro-inflammatory cytokines like TNF-alpha by T cells potentially causing atopic dermatitis.[22] It is thought that by understanding the mechanism of TSLP production and those potential substances that block the production, one may be able to prevent or treat conditions of asthma and/or eczema.[25]

Therapeutic targeting

The TSLP signaling axis is an attractive therapeutic target. Amgen's Tezepelumab, a monoclonal antibody which blocks TSLP, is currently approved for the treatment of severe asthma.[26][27] Fusion proteins consisting of TSLPR and IL-7Rα which can trap TSLP with excellent affinity have also been designed.[18] Additional approaches towards TSLP/TSLPR inhibition include peptides derived from the TSLP:TSLPR interface,[28] natural products [29] and computational fragment-based screening.[30]

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 "Role of thymic stromal lymphopoietin in allergy and beyond". Nature Reviews. Immunology 23 (1): 24–37. January 2023. doi:10.1038/s41577-022-00735-y. PMID 35650271. 
  2. ↑ 2.0 2.1 "Thymic Stromal Lymphopoietin: To Cut a Long Story Short". Cellular and Molecular Gastroenterology and Hepatology 3 (2): 174–182. March 2017. doi:10.1016/j.jcmgh.2017.01.005. PMID 28275684. 
  3. ↑ "Thymic Stromal Lymphopoietin Improves Survival and Reduces Inflammation in Sepsis". American Journal of Respiratory Cell and Molecular Biology 55 (2): 264–274. August 2016. doi:10.1165/rcmb.2015-0380OC. PMID 26934097. 
  4. ↑ "TSLP: from allergy to cancer". Nature Immunology 20 (12): 1603–1609. December 2019. doi:10.1038/s41590-019-0524-9. PMID 31745338. 
  5. ↑ "Cloning of human thymic stromal lymphopoietin (TSLP) and signaling mechanisms leading to proliferation". Leukemia 15 (8): 1286–1292. August 2001. doi:10.1038/sj.leu.2402175. PMID 11480573. 
  6. ↑ 6.0 6.1 "Entrez Gene: TSLP thymic stromal lymphopoietin". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=85480. 
  7. ↑ 7.0 7.1 7.2 "Functional analysis of the thymic stromal lymphopoietin variants in human bronchial epithelial cells". American Journal of Respiratory Cell and Molecular Biology 40 (3): 368–374. March 2009. doi:10.1165/rcmb.2008-0041OC. PMID 18787178. 
  8. ↑ "A thymic stromal cell line supports in vitro development of surface IgM+ B cells and produces a novel growth factor affecting B and T lineage cells". Experimental Hematology 22 (3): 321–328. March 1994. PMID 8112430. https://pubmed.ncbi.nlm.nih.gov/8112430/. 
  9. ↑ 9.0 9.1 "Dichotomy of short and long thymic stromal lymphopoietin isoforms in inflammatory disorders of the bowel and skin". The Journal of Allergy and Clinical Immunology 136 (2): 413–422. August 2015. doi:10.1016/j.jaci.2015.04.011. PMID 26014813. 
  10. ↑ "Distinct roles of short and long thymic stromal lymphopoietin isoforms in house dust mite-induced asthmatic airway epithelial barrier disruption". Scientific Reports 6 (1): 39559. December 2016. doi:10.1038/srep39559. PMID 27996052. Bibcode: 2016NatSR...639559D. 
  11. ↑ "Thymic Stromal Lymphopoietin (TSLP), Its Isoforms and the Interplay with the Epithelium in Allergy and Asthma". International Journal of Molecular Sciences 24 (16): 12725. August 2023. doi:10.3390/ijms241612725. PMID 37628907. 
  12. ↑ "Mast cells instruct keratinocytes to produce thymic stromal lymphopoietin: Relevance of the tryptase/protease-activated receptor 2 axis". The Journal of Allergy and Clinical Immunology 149 (6): 2053–2061.e6. June 2022. doi:10.1016/j.jaci.2022.01.029. PMID 35240143. 
  13. ↑ "IL-33 and Thymic Stromal Lymphopoietin in mast cell functions". European Journal of Pharmacology. Pharmacological modulation of Mast cells and Basophils 778: 68–76. May 2016. doi:10.1016/j.ejphar.2015.04.047. PMID 26051792. 
  14. ↑ Poulsen, Lars K.; Hummelshoj, Lone (July 2009). "Triggers of IgE class switching and allergy development" (in en). Annals of Medicine 39 (6): 440–456. doi:10.1080/07853890701449354. ISSN 0785-3890. PMID 17852040. http://www.tandfonline.com/doi/full/10.1080/07853890701449354. 
  15. ↑ 15.0 15.1 "Type III interferon exerts thymic stromal lymphopoietin in mediating adaptive antiviral immune response". Frontiers in Immunology 14: 1250541. 2023-09-22. doi:10.3389/fimmu.2023.1250541. PMID 37809098. 
  16. ↑ Victora, Gabriel D.; Nussenzweig, Michel C. (2022-04-26). "Germinal Centers" (in en). Annual Review of Immunology 40 (1): 413–442. doi:10.1146/annurev-immunol-120419-022408. ISSN 0732-0582. PMID 35113731. https://www.annualreviews.org/doi/10.1146/annurev-immunol-120419-022408. 
  17. ↑ Domeier, Phillip P.; Rahman, Ziaur S.M.; Ziegler, Steven F. (2023-01-06). "B- and T-cell-intrinsic regulation of germinal centers by thymic stromal lymphopoietin signaling". Science Immunology 8 (79): eadd9413. doi:10.1126/sciimmunol.add9413. ISSN 2470-9468. PMID 36608149. 
  18. ↑ 18.0 18.1 PDB: 5J11​; "Structure and antagonism of the receptor complex mediated by human TSLP in allergy and asthma". Nature Communications 8: 14937. April 2017. doi:10.1038/ncomms14937. PMID 28368013. Bibcode: 2017NatCo...814937V. 
  19. ↑ "Requirement for stat5 in thymic stromal lymphopoietin-mediated signal transduction". Journal of Immunology 163 (11): 5971–5977. December 1999. doi:10.4049/jimmunol.163.11.5971. PMID 10570284. 
  20. ↑ "Thymic stromal lymphopoietin expression is increased in asthmatic airways and correlates with expression of Th2-attracting chemokines and disease severity". Journal of Immunology 174 (12): 8183–8190. June 2005. doi:10.4049/jimmunol.174.12.8183. PMID 15944327. 
  21. ↑ "A possible role for TSLP in inflammatory arthritis". Biochemical and Biophysical Research Communications 357 (1): 99–104. May 2007. doi:10.1016/j.bbrc.2007.03.081. PMID 17416344. 
  22. ↑ 22.0 22.1 "Thymic stromal lymphopoietin converts human epidermal Langerhans cells into antigen-presenting cells that induce proallergic T cells". The Journal of Allergy and Clinical Immunology 119 (4): 982–990. April 2007. doi:10.1016/j.jaci.2007.01.003. PMID 17320941. 
  23. ↑ "Human thymic stromal lymphopoietin: a novel epithelial cell-derived cytokine and a potential key player in the induction of allergic inflammation". Springer Seminars in Immunopathology 25 (3–4): 325–333. February 2004. doi:10.1007/s00281-003-0152-0. PMID 14999427. 
  24. ↑ "Human epithelial cells trigger dendritic cell mediated allergic inflammation by producing TSLP". Nature Immunology 3 (7): 673–680. July 2002. doi:10.1038/ni805. PMID 12055625. https://eprints.ucm.es/id/eprint/9340/1/17.Soumelis_Reche_etal_NI_2002.pdf. 
  25. ↑ "Skin-derived TSLP triggers progression from epidermal-barrier defects to asthma". PLOS Biology 7 (5): e1000067. May 2009. doi:10.1371/journal.pbio.1000067. PMID 19557146. 
  26. ↑ "Tezspire- tezepelumab-ekko injection, solution". https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=60f0aa03-ad25-4d48-80ce-7fcfa76f325f. 
  27. ↑ "Tezspire (tezepelumab) approved in the US for severe asthma". AstraZeneca (Press release). 17 December 2021. Retrieved 17 December 2021.
  28. ↑ "Synthesis and biological evaluation of peptide-derived TSLP inhibitors". Bioorganic & Medicinal Chemistry Letters 27 (20): 4710–4713. October 2017. doi:10.1016/j.bmcl.2017.09.010. PMID 28927768. 
  29. ↑ "Structure-Activity Relationships of Baicalein and its Analogs as Novel TSLP Inhibitors". Scientific Reports 9 (1): 8762. June 2019. doi:10.1038/s41598-019-44853-5. PMID 31217492. Bibcode: 2019NatSR...9.8762P. 
  30. ↑ "Virtual screening for inhibitors of the human TSLP:TSLPR interaction". Scientific Reports 7 (1): 17211. December 2017. doi:10.1038/s41598-017-17620-7. PMID 29222519. Bibcode: 2017NatSR...717211V. 

External links

  • Overview of all the structural information available in the PDB for UniProt: Q969D9 (Thymic stromal lymphopoietin) at the PDBe-KB.



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