Chemokine CXCL13 is essential for lymph node initiation and is induced by retinoic acid and neuronal stimulation

Pavert, Serge A. van de; Olivier, Brenda J.; Goverse, Gera; Vondenhoff, M.F.R.; Greuter, Mascha; Beke, Patrick; Kusser, Kim; Höpken, Uta E.; Lipp, Martin; Niederreither, Karen; Blomhoff, Rune; Sitnik, Katarzyna; Agace, William W.; Randall, Troy D.; Jonge, Wouter J. de; Mebius, Reina E.

doi:10.1038/ni.1789

Cited by 269 publications

(279 citation statements)

References 51 publications

(78 reference statements)

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“…Here, we show that CXCL13 is produced by Schwannian stromal cells adding new information about the factors released by stroma of neuroblastic tumors and we suggest a relevant role of the CXCL13/CXCR5b axis in the crosstalk between neuroblasts and stromal cells. The novel discovery that Schwannian stromal cells express CXCL13 supports the previous findings that cells of neural origin are able to produce CXCL13 (23,24).…”

Section: Discussionsupporting

confidence: 75%

Role of CXCL13-CXCR5 Crosstalk Between Malignant Neuroblastoma Cells and Schwannian Stromal Cells in Neuroblastic Tumors

Grosso

Coco

Scaruffi

et al. 2011

Molecular Cancer Research

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Neuroblastoma is a stroma-poor (SP) aggressive pediatric cancer belonging to neuroblastic tumors, also including ganglioneuroblastoma and ganglioneuroma, two stroma-rich (SR) less aggressive tumors. Our previous gene-expression profiling analysis showed a different CXCL13 mRNA expression between SP and SR tumors. Therefore, we studied 13 SP and 13 SR tumors by reverse transcription quantitative real-time PCR (RT-qPCR) and we found that CXCR5b was more expressed in SP than in SR and CXCL13 was predominantly expressed in SR tumors. Then, we isolated neuroblastic and Schwannian stromal cells by laser capture microdissection and we found that malignant neuroblasts express CXCR5b mRNA, whereas Schwannian stromal cells express CXCL13. Immunohistochemistry confirmed that stroma expresses CXCL13 but not CXCR5. To better understand the role of CXCL13 and CXCR5 in neuroblastic tumors we studied 11 neuroblastoma cell lines and we detected a heterogeneous expression of CXCL13 and CXCR5b. Interestingly, we found that only CXCR5b splice variant was expressed in both tumors and neuroblastoma lines, whereas CXCR5a was never detected. Moreover, we found that neuroblastoma cells expressing CXCR5 receptor migrate toward a source of recombinant CXCL13. Lastly, neuroblastoma cells induced to glial cell differentiation expressed CXCL13 mRNA and protein. The chemokine released in the culture medium was able to stimulate chemotaxis of LA1-5S neuroblastoma cells. Collectively, our data suggest that CXCL13 produced by stromal cells may contribute to the generation of an environment in which the malignant neuroblasts are retained, thus limiting the possible development of metastases in patients with SR tumor. Mol Cancer Res; 9(7); 815-23. '2011 AACR.

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Section: Discussionsupporting

confidence: 75%

Role of CXCL13-CXCR5 Crosstalk Between Malignant Neuroblastoma Cells and Schwannian Stromal Cells in Neuroblastic Tumors

Grosso

Coco

Scaruffi

et al. 2011

Molecular Cancer Research

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“…A recent report demonstrates, in striking similarity to our findings, that immune cells cluster around nerves in developing lymph nodes and that vagus nerve stimulation induces the expression of chemokines via retinoic acid (RA) (39). RA is a potent inducer of adhesion molecule expression and a regulator of leukocyte trafficking by this mechanism (40,41).…”

Section: Discussionsupporting

confidence: 62%

Neural Signaling in the Spleen Controls B-Cell Responses to Blood-Borne Antigen

Mina‐Osorio

Rosas-Ballina

Valdés-Ferrer

et al. 2012

Mol Med

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Entry of blood-borne pathogens into the spleen elicits a series of changes in cellular architecture that culminates in the systemic release of protective antibodies. Despite an abundance of work that has characterized these processes, the regulatory mechanisms that coordinate cell trafficking and antibody production are still poorly understood. Here, marginal zone (MZ) B cells responding to streptococcus in the blood were observed to migrate along splenic nerves, arriving at the red pulp venous sinuses where they become antibody-secreting cells. Electrical stimulation of the vagus nerve, which in turn regulates the splenic nerve, arrested B-cell migration and decreased antibody secretion. Thus, neural circuits regulate the first wave of antibody production following B-cell exposure to blood-borne antigen.

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“…24 -26 In embryonic lymph node development, stimulation of neurons elicits retinoic acid production leading to CXCL13 expression by lymph node organizer cells, thus triggering the initial formation of the lymph node anlagen without a requirement for LT-␣. 27 CXCL13 also contributes to the formation of B-cell follicles in nasopharynx-associated lymphoid tissue and omental milky spots. 28,29 Intestinal CPs and ILFs also depend on CXCL13 for B-cell recruitment and maturation into ILFs.…”

Section: Discussionmentioning

confidence: 99%

Distinct Developmental Requirements for Isolated Lymphoid Follicle Formation in the Small and Large Intestine

Knoop

Butler

Kumar

et al. 2011

The American Journal of Pathology

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Cryptopatches (CPs) and isolated lymphoid follicles (ILFs) are organized intestinal lymphoid tissues that develop postnatally in mice and include stromal cells expressing the receptor activator of nuclear factor kappa-B ligand (RANKL). We investigated how stromal RANKL influences the development and differentiation of CPs and ILFs by analyzing the development of these lymphoid structures in knockout mice lacking RANKL. We found that RANKL ؊/؊ mice had a fourfold reduction in the overall density of CPs in the small intestine compared to control mice, with the largest decrease in the proximal small intestine. No B cells were present in CPs from the small intestine of RANKL ؊/؊ mice and ILF formation was completely blocked. In sharp contrast, colonic ILFs containing B cells were present in RANKL ؊/؊ mice. Stromal cells within CPs in the small intestine of RANKL ؊/؊ mice did not express CXCL13 (originally called B lymphocyte chemoattractant) and often lacked other normally expressed stromal cell antigens, whereas colonic lymphoid aggregates in RANKL ؊/؊ mice retained stromal CXCL13 expression. The CXCL13-dependent maturation of precursor CPs into ILFs is differentially regulated in the small intestine and colon, with an absolute requirement for RANKL only in the small intestine.

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Chemokine CXCL13 is essential for lymph node initiation and is induced by retinoic acid and neuronal stimulation

Cited by 269 publications

References 51 publications

Role of CXCL13-CXCR5 Crosstalk Between Malignant Neuroblastoma Cells and Schwannian Stromal Cells in Neuroblastic Tumors

Role of CXCL13-CXCR5 Crosstalk Between Malignant Neuroblastoma Cells and Schwannian Stromal Cells in Neuroblastic Tumors

Neural Signaling in the Spleen Controls B-Cell Responses to Blood-Borne Antigen

Distinct Developmental Requirements for Isolated Lymphoid Follicle Formation in the Small and Large Intestine

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