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

Prete, Annalisa Del; Shao, Wen; Mitola, Stefania; Santoro, Giuseppe; Sozzani, Silvano; Haribabu, Bodduluri

doi:10.1182/blood-2006-02-003665

Cited by 111 publications

(101 citation statements)

References 30 publications

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“…Compared to immature DCs, mature DCs expressed higher levels of MHCII, CD86, and CCR7, as expected (32). Finally, we found that autologous secretion of CCL19 (33), which could potentially interfere with exogenous gradient sensing, was at least an order of magnitude less than the average concentrations of added chemokines (Fig. S2F), allowing us to consider only the exogenous gradients in interpreting the results.…”

Section: Resultsmentioning

confidence: 67%

Dendritic cell chemotaxis in 3D under defined chemokine gradients reveals differential response to ligands CCL21 and CCL19

Haessler

Pisano

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

181

184

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Dendritic cell (DC) homing to the lymphatics and positioning within the lymph node is important for adaptive immunity, and is regulated by gradients of CCL19 and CCL21, ligands for CCR7. Despite the importance of DC chemotaxis, it is not well understood how DCs interpret gradients of these chemokines in a complex 3D microenvironment. Here, we use a microfluidic device that allows rapid establishment of stable gradients in 3D matrices to show that DC chemotaxis in 3D can respond to CCR7 ligand gradients as small as 0.4%, which helps explain how DCs sense lymphatic vessels in an environment where broadcast distance for chemokine diffusion is hindered by convective flows into the vessel. Interestingly, DCs displayed similar sensitivities to both chemokines at small gradients (≤60 nM∕mm), but migrated more efficiently towards higher gradients of CCL21, which unlike CCL19 binds strongly to matrix proteoglycans and signals without the need for internalization. Furthermore, cells preferentially migrated towards CCL21 when exposed to equal and opposite gradients of CCL21 and CCL19 simultaneously, even when matrix-binding of CCL21 was prevented. Although these ligands have similar binding affinity to CCR7, our results demonstrate that, in a 3D environment, CCL21 is a more potent directional cue for DC migration than CCL19. These findings provide new quantitative insight into DC chemotaxis in a physiological 3D environment and suggest how CCL19 and CCL21 may signal differently to fine-tune DC homing and positioning within the lymphatic system. These results also have broad relevance to other systems of cell chemotaxis, which remain poorly understood in the 3D context.D endritic cells (DCs) are considered the most potent and professional antigen-presenting cells. DCs are positioned throughout the periphery, and when activated, migrate to lymphatic vessels and into lymph nodes, where they can direct antigen-specific Tcell responses. Upon activation or maturation, DCs upregulate the C-C chemokine-receptor CCR7, which allows them to sense and home towards CCR7 ligand-secreting lymphatic vessels and lymph nodes (1). The two known ligands for CCR7 are the C-C chemokines CCL21 and CCL19 (2); both are secreted by stromal cells in the lymph node paracortex to properly position DCs with CCR7 þ naïve T cells for their activation. CCL21, but not CCL19, is also expressed by the endothelium of lymphatic vessels in the periphery (1). Thus, CCR7-mediated chemotaxis is critical for DC homing to, and positioning within, lymph nodes and for T cell activation there (3).CCL19 and CCL21 function as directional signals presumably by virtue of concentration gradients (∇C) that guide DCs towards areas of increasing concentrations. Interestingly, CCL19 and CCL21 have similar binding affinities for CCR7 (4-6) and similar chemotactic potential for DCs and T cells under 2D conditions (7,8), but differ in their internalization (8, 9) as well as their binding affinity to extracellular matrix (ECM) proteoglycans. Specifically, the positively charged C t...

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Section: Resultsmentioning

confidence: 67%

Dendritic cell chemotaxis in 3D under defined chemokine gradients reveals differential response to ligands CCL21 and CCL19

Haessler

Pisano

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

181

184

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“…However, the role for this receptor on DCs in the development of AHR and inflammation has not been defined. Evidence for expression of a functional BLT1 receptor on DCs was provided by Del Prete et al (34), who showed that murine DCs mobilize calcium and chemotaxis in response to LTB 4 and that BLT1 expression on DC regulates delayed-type hypersensitivity in the skin. Here, we confirm that DCs in the lungs, regional lymph nodes, and airways express BLT1 and that expression of BLT1 on DCs can play an important role in the development of allergen-induced AHR and inflammation.…”

Section: Discussionmentioning

confidence: 99%

“…The migration of Ag-pulsed DCs into peripheral tissues has been shown to be dependent on the expression of CCR7 by DCs and the production of CCR7 ligands, CCL19, by stromal cells and mature DCs in the lymph node, and CCL21 by afferent lymphatic cells. Del Prete et al reported that LTB 4 up-regulates CCR7 expression and function and that this effect is primarily through the enhancement of chemotaxis with only a minor effect on chemokinesis (34). They showed that chemotaxis of BLT1 Ϫ/Ϫ BMDCs in response to CCL19 and CCL21 was significantly impaired compared with BLT1 ϩ/ϩ BMDCs, that LTB 4 -induced migration of immature DCs to CCL19 and CCL21 was associated with an increase in CCR7 membrane expression, and that LTB 4 up-regulates the migration of mature DCs to CCR7 ligands.…”

Section: Discussionmentioning

confidence: 99%

Leukotriene B4 Receptor 1 Expression on Dendritic Cells Is Required for the Development of Th2 Responses and Allergen-Induced Airway Hyperresponsiveness

Miyahara

Ohnishi

Matsuda

et al. 2008

The Journal of Immunology

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Dendritic cells (DC) are important APCs that control allergen-induced airway responses by interacting directly with T cells. Leukotriene B4 (LTB4), interacting with its high-affinity receptor, LTB4 receptor 1 (BLT1), is known to attract and activate leukocytes during inflammation. We have previously shown that BLT1 expression on Ag-primed T cells is required for the development of airway hyperresponsiveness (AHR; Miyahara et al. 2005. Am. J. Respir. Crit. Care Med. 172: 161–167). However, the role for the LTB4-BLT1 pathway in DC function in allergen-induced airway responses has not been defined. Bone marrow-derived DCs (BMDC) were generated. Naive BALB/c mice received OVA-pulsed BLT1-deficient (BLT1−/−) BMDCs or wild-type BMDCs intratracheally and were then challenged with OVA for 3 days. Airway responses were monitored 48 h after the last allergen challenge. BLT1−/− BMDCs showed normal maturation judged from surface expression of CD markers. Compared with recipients of wild-type BMDCs, mice that received BLT1−/− BMDCs developed significantly lower AHR to inhaled methacholine, lower goblet cell metaplasia, and eosinophilic infiltration in the airways and decreased levels of Th2 type cytokines in the bronchoalveolar lavage fluid. Migration of BLT1−/− BMDCs into peribronchial lymph nodes was significantly impaired compared with BLT1+/+ BMDCs after intratracheal instillation. These data suggest that BLT1 expression on DCs is required for migration of DCs to regional lymph nodes as well as in the development of AHR and airway inflammation.

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“…Although BLT1 was long known to be a neutrophil chemoattractant receptor, recent studies identified BLT1 expression on macrophages [22], smooth muscle cells [23], endothelial cells [24], activated T-cells [25] and mast cells [26] considerably expanding the potential role of LTB 4 . Recent experiments from our laboratory demonstrated functional expression of BLT1 on both mature and immature dendritic cells and having a direct effect in the control of adaptive immune responses [27]. Knockout mice for BLT1 generated in several laboratories have been instrumental in defining a critical role for this receptor in diverse inflammatory diseases such as atherosclerosis [22] asthma, autoimmune uveitis and arthritis (see below).…”

Section: Leukotriene B 4 and Its Receptorsmentioning

confidence: 99%

Role of leukotriene B4 receptors in rheumatoid arthritis

Mathis

Jala

Haribabu

2007

Autoimmunity Reviews

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The purpose of this review is to summarize the role that murine models of arthritis are playing in the understanding of human rheumatoid arthritis and how leukotriene B 4 (LTB 4 ) is emerging as an important target in this field. Both the collagen-induced arthritis (CIA) model and the K/BxN serum transfer arthritis model have contributed to outline the potential mechanisms involved in inflammatory arthritis. Indeed, the CIA model has contributed to the development of effective anti-TNF and anti-IL-1β based treatments for RA that are currently in the clinic. Many recent studies in mouse models have suggested a critical role for LTB 4 and its receptors in the development of inflammatory arthritis. Inhibitors of LTB 4 biosynthesis as well as LTB 4 receptors are protective in mouse models of RA and mice deficient in the LTB 4 biosynthetic enzymes or LTB 4 receptors are resistant to disease development suggesting several promising targets for RA in this pathway. KeywordsRheumatoid Arthritis; Leukotriene B4 receptors; arthritis mouse models; FLAP Take home message• Mouse models of RA have provided a great deal of information on the mechanisms involved in human RA and led to the development of effective therapies and are likely to uncover additional therapeutic opportunities • Chemoattractants and cytokines form important amplification loops for perpetual joint inflammation in RA • Inhibition of inflammatory cell recruitment to the rheumatoid synovium represents a potential target for RA treatment.• LTB 4 and its receptors play a critical role in the recruitment of leucocytes to the inflammatory sites. Mice lacking either the enzymes involved in LTB 4 biosynthesis or the LTB 4 receptors are completely protected from the development of RA.• Unraveling the mechanisms of LTB 4 /BLT1 and LTB 4 /BLT2 axis and structure/ function of BLT1 and BLT2 will provide important insights into identification of novel and dual antagonists for blocking their function.

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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

Cited by 111 publications

References 30 publications

Dendritic cell chemotaxis in 3D under defined chemokine gradients reveals differential response to ligands CCL21 and CCL19

Dendritic cell chemotaxis in 3D under defined chemokine gradients reveals differential response to ligands CCL21 and CCL19

Leukotriene B4 Receptor 1 Expression on Dendritic Cells Is Required for the Development of Th2 Responses and Allergen-Induced Airway Hyperresponsiveness

Role of leukotriene B4 receptors in rheumatoid arthritis

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