Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Research Highlight
  • Published:

Inflammatory bowel disease: DCs sense LTB4 to drive TH1 and TH17 differentiation

Cellular & Molecular Immunology volume 17, pages 307–309 (2020)Cite this article

Ulcerative colitis and Crohn’s disease are the two major forms of inflammatory bowel disease (IBD) in humans.1 Chronic human IBD, such as Crohn’s disease, is characterized by features such as intestinal infiltration of immune cells, inflammatory cytokine milieu, intestinal fibrosis and weight loss among others, that lead to chronic and spontaneously recurring intestinal inflammation.2 Several mouse models of IBD have been used by researchers to understand the diverse aspects related to human IBD.1,2 For example, the mouse model of intra-rectal administration of the haptenating agent, 2,4,6-trinitrobenzene sulfonic acid (TNBS), which induces mucosal immunity to colonic immunogenic proteins in the host, recapitulates key immunological responses observed in Crohn’s disease, such as cytokine secretion patterns, intestinal fibrosis, and immune intolerance.2 The innate immune response is critical to initiate the cytokines production that prime T-cell differentiation in the TNBS model. The polarized T-cell responses are hallmarks of IBD and in the TNBS model TH1 and TH17-cell responses predominate as is observed with the signature cytokine secretion profile of IL12/IFNγ and IL23/IL17, respectively.2

Given the ability of dendritic cells (DCs) to modulate T-cell differentiation by secreting the key cytokines, exploring the recruitment, activation, roles and targeting of DCs in chronic IBD has been of considerable interest.3 Among the non-chemokine chemoattractants, DCs are well known to respond to the lipid mediator, Leukotriene B4 (LTB4).4 LTB4 is a potent chemoattractant produced in response to inflammation, largely by the cells of the myeloid lineage and to a lesser extent by the other immune and non-immune cells.5,6 The cognate G-protein coupled receptor (GPCR) for LTB4, BLT1, is expressed predominantly by the cells of the myeloid lineage and to a lesser extent by the other immune and non-immune cells.5,6 The binding of LTB4 to BLT1 activates the pathways leading to adhesion, polarization, and migration of target cells.6 Indeed, the LTB4-BLT1 signaling is required for the effective recruitment of neutrophils, macrophages and other myeloid-derived cells to the site of inflammation. In addition, the LTB4-BLT1 axis can also promote the recruitment of lymphocytes to the inflammation site in specific mouse models.5,6 Human monocyte-derived DCs that express BLT2 but not BLT1, are known to chemotax in response to LTB4.7 Importantly, the bone-marrow derived DCs from mouse respond to LTB4 by upregulating the chemokine GPCR CCR7, which binds and is activated by CCL19 and CCL21, and lack of BLT1 in such DCs impairs their ability to home to the draining lymph nodes.8 Additionally, LTB4-driven migration of DCs is important for the generation of TH2 type responses to airway hyperresponsiveness, which is dampened in the absence of BLT1 on DCs.9 Furthermore, lack of BLT1 in DCs dampens their ability to skew T-cell polarization to TH1 type in a mouse model of delayed-type hypersensitivity.10 Clearly, LTB4 acts on DCs to mediate two important and distinct cellular responses—(1) recruitment to the site of inflammation and (2) secretion of cytokines to skew T-cell polarization. However, the precise role of the LTB4-BLT1 axis in DC response in the context of IBD was not previously explored.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1

References

  1. Mizoguchi, A. Animal models of inflammatory bowel disease. Prog. Mol. Biol. Transl. Sci. 105, 263–320 (2012).

    Article  CAS  Google Scholar 

  2. Kiesler, P., Fuss, I. J. & Strober, W. Experimental models of inflammatory bowel diseases. Cell Mol. Gastroenterol. Hepatol. 1, 154–170 (2015).

    Article  Google Scholar 

  3. Kaistha, A. & Levine, J. Inflammatory bowel disease: the classic gastrointestinal autoimmune disease. Curr. Probl. Pediatr. Adolesc. Health Care 44, 328–334 (2014).

    Article  Google Scholar 

  4. Tiberio, L., et al. Chemokine and chemotactic signals in dendritic cell migration. Cell Mol Immunol. 15, 346–352 (2018).

  5. Yokomizo, T. Two distinct leukotriene B4 receptors, BLT1 and BLT2. J. Biochem. 157, 65–71 (2015).

    Article  CAS  Google Scholar 

  6. Subramanian, B. C., Majumdar, R. & Parent, C. A. The role of the LTB4-BLT1 axis in chemotactic gradient sensing and directed leukocyte migration. Semin. Immunol. 33, 16–29 (2017).

    Article  CAS  Google Scholar 

  7. Shin, E. H., Lee, H. Y. & Bae, Y. S. Leukotriene B4 stimulates human monocyte-derived dendritic cell chemotaxis. Biochem. Biophys. Res. Commun. 348, 606–611 (2006).

    Article  CAS  Google Scholar 

  8. Del Prete, A. et al. Regulation of dendritic cell migration and adaptive immune response by leukotriene B4 receptors: a role for LTB4 in up-regulation of CCR7 expression and function. Blood 109, 626–631 (2007).

    Article  Google Scholar 

  9. Miyahara, N. et al. Leukotriene B4 receptor 1 expression on dendritic cells is required for the development of Th2 responses and allergen-induced airway hyperresponsiveness. J. Immunol. 181, 1170–1178 (2008).

    Article  CAS  Google Scholar 

  10. Toda, A. et al. Attenuated Th1 induction by dendritic cells from mice deficient in the leukotriene B4 receptor 1. Biochimie 92, 682–691 (2010).

    Article  CAS  Google Scholar 

  11. Zhou, J., et al. BLT1 in dendritic cells promotes Th1/Th17 differentiation and its deficiency ameliorates TNBS-induced colitis. Cell Mol Immunol. 2018 Apr 18 https://doi.org/10.1038/s41423-018-0030-2. PMID: 29670278.

  12. Cuzzocrea, S. et al. 5-Lipoxygenase modulates colitis through the regulation of adhesion molecule expression and neutrophil migration. Lab. Invest. 85, 808–822 (2005).

    Article  CAS  Google Scholar 

  13. Afonso, P. V. et al. LTB4 is a signal-relay molecule during neutrophil chemotaxis. Dev. Cell 22, 1079–1091 (2012).

    Article  CAS  Google Scholar 

  14. Lammermann, T. et al. Neutrophil swarms require LTB4 and integrins at sites of cell death in vivo. Nature 498, 371–375 (2013).

    Article  Google Scholar 

Download references

Acknowledgements

Dr. Christina Stuelten is thanked for her constructive inputs on this write-up. This work was supported by the Intramural Research Program of the Center for Cancer Research, NCI, National Institutes of Health.

Author information

Authors and Affiliations

  1. Laboratory of Cellular and Molecular Biology, National Cancer Institute, NIH, Bethesda, MD, 20892, USA

    Bhagawat C. Subramanian

Authors
  1. Bhagawat C. Subramanian
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Bhagawat C. Subramanian.

Ethics declarations

Competing interests

The author declares no competing interests.

Additional information

Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Subramanian, B.C. Inflammatory bowel disease: DCs sense LTB4 to drive TH1 and TH17 differentiation. Cell Mol Immunol 17, 307–309 (2020). https://doi.org/10.1038/s41423-018-0162-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41423-018-0162-4

Keywords

This article is cited by

Search

Advanced search

Quick links