Monocyte-like and mature macrophages produce CXCL13 (B cell–attracting chemokine 1) in inflammatory lesions with lymphoid neogenesis

Abstract

IntroductionRheumatoid arthritis (RA) and ulcerative colitis (UC) are chronic inflammatory diseases associated with de novo formation of irregular T-and B-cell aggregates in the synovium 1 and large bowel mucosa, 2 respectively. Such local development of lymphoid tissue is thought to contribute to the pathology of chronic inflammation. 3,4 Lymphoid tissue organization is orchestrated by a subset of the chemokine family, termed homeostatic or lymphoid chemokines because of their constitutive expression in secondary lymphoid tissues. 5 One of these lymphoid chemokines, CXCL13, also called B cell-attracting chemokine 1 (BCA-1) 6 or B-lymphocyte chemoattractant (BLC), 7 and its receptor CXCR5, also called Burkitt lymphoma receptor-1 (BLR1), are required for normal development of secondary lymphoid organs in mice. 8,9 CXCL13 and CXCR5 have, in addition, been detected in various chronic human inflammatory diseases where lymphoid neogenesis occurs, such as Helicobacter pylori gastritis, 10 RA, 1,11 Sjögren syndrome, 12-14 and UC 15 as well as in gastric 10 and primary central nervous system lymphoma. 16 Follicular dendritic cells (FDCs) are generally believed to be the main source of CXCL13 in normal 6,7,17 as well as inflamed lymphoid tissue. 1,10,11 In addition, vascular expression of the CXCL13 protein has been reported, 1,15,16,18,19 and CXCL13 and CXCR5 have been shown to play an important role in B-cell homing to murine Peyer patches. 20 However, no expression analysis of CXCL13 mRNA in human lymphoid tissue 10,15,16,18 has directly shown that CXCL13 is actually produced by FDCs or endothelial cells. Importantly, available data do not exclude the possibility that murine FDCs in fact bind CXCL13 rather than produce it. 7,17 Also of note, CXCL13 protein is undetectable in human FDC-like cells stimulated in vitro. 21 We have shown earlier that another lymphoid chemokine, CCL19, is present and functions in endothelial cells that are not its source. 22 In our recent human study of normal and aberrant gutassociated lymphoid tissue, we found that CXCL13 was mainly associated with extracellular fibrils and only minimally with cells displaying the traditional FDC phenotype. 15 This prompted us to explore more extensively the source of this chemokine in human lymphoid neogenesis represented by RA synovium and UC large bowel mucosa. Furthermore, we investigated the potential mechanistic role monocyte-derived cells could play in CXCL13 secretion. Our data documented for the first time that human monocytes/ macrophages are a potent inducible source of CXCL13 and, in fact, appear to be the main producers of this chemokine in inflammatory lesions where lymphoid neogenesis occurs. This suggested a role of recently extravasated macrophages in the formation of such ectopic follicles. Patients, materials, and methods PatientsClinicopathologic data and patient treatment schedules are provided in Table 1. Cryosections (8 m) were cut serially from various human tissue For personal use only. on May 10, 2018. by guest www.bloodjournal.o...

Systematic microanatomical analysis of CXCL13 and CCL21 in situ production and progressive lymphoid organization in rheumatoid synovitis

“…4A-F), confirming that neither the follicular structure nor the environment of a Grade 3 cluster is necessary for CXCL13 production within the synovial lymphoid tissue. This phenomenon, which we previously reported in a published abstract [27], was recently confirmed independently by Carlsen et al [19]. They also extended this observation by demonstrating, in agreement with the work of Perrier et al [28], that CXCL13 can be produced by non-stromal hemopoietic cells of the monocyte lineage.…”

“…The concept that CXCL13 and CCL21 may also be involved in human ectopic lymphoid tissue organization is supported by their detection in several chronic inflammatory conditions including rheumatoid arthritis (RA) [17][18][19][20][21][22]. An attempt to define the functional roles of CXCL13 and CCL21 in synovial lymphoid neogenesis in RA was made by Takemura et al [18], who examined the relationship between mRNA levels of CXCL13 and CCL21 on homogenized synovial tissues and the organizational pattern of the inflammatory infiltrate.…”

Chronic Rejection Triggers the Development of an Aggressive Intragraft Immune Response through Recapitulation of Lymphoid Organogenesis

“…Indeed, among the molecular checkpoints, critical for the completion of the lymphoid neogenesis program, that we have identified, LTbR represents an attractive therapeutic target. LTbR signaling primes the expression of homeostatic chemokines in stromal cells (30), and therefore plays a critical role in the recruitment and subsequent organization of inflammatory effectors within the diseased tissue (6,(31)(32)(33)(34)(35). Our findings, which demonstrate that LTbR expression is characteristic of samples from the C4 cluster, indicate that its role is not restricted to the early stages of the ontogeny of lymphoid organs; it also extends to the maintenance of lymphoid-tissue architecture as proposed by Browning et al (36).…”

CXCR5‐ and CCR7‐dependent lymphoid neogenesis in a murine model of chronic antigen‐induced arthritis

“…Therefore, depletion of CXCR5 could reduce the number of lymphocytes that are recruited through CXCL13 into the synovial tissue, which are normally expressed in the B cell areas by follicular dendritic cells (19) but might also be expressed by monocytes and macrophages (41). However, our group recently showed 3280 WENGNER ET AL that tonsillar CXCR5 high , ICOS high follicular B helper T cells are an efficient source of secreted CXCL13 (42).…”