Human Lymph Node-Derived Fibroblastic and Double-Negative Reticular Cells Alter Their Chemokines and Cytokines Expression Profile Following Inflammatory Stimuli

Abstract

Lymph node (LN) is a secondary lymphoid organ with highly organized and compartmentalized structure. LNs harbor B, T, and other cells among fibroblastic reticular cells (FRCs). FRCs are characterized by both podoplanin (PDPN/gp38) expression and by the lack of CD31 expression. FRCs are involved in several immune response processes but mechanisms underlying their function are still under investigation. Double-negative cells (DNCs), another cell population within LNs, are even less understood. They do not express PDPN or CD31, their localization within the LN is unknown, and their phenotype and function remain to be elucidated. This study evaluates the gene expression and cytokines and chemokines profile of human LN-derived FRCs and DNCs during homeostasis and following inflammatory stimuli. Cytokines and chemokines secreted by human FRCs and DNCs partially diverged from those identified in murine models that used similar stimulation. Cytokine and chemokine secretion and their receptors expression levels differed between stimulated DNCs and FRCs, with FRCs expressing a broader range of chemokines. Additionally, dendritic cells demonstrated increased migration toward FRCs, possibly due to chemokine-induced chemotaxis since migration was significantly decreased upon neutralization of secreted CCL2 and CCL20. Our study contributes to the understanding of the biology and functions of FRCs and DNCs and, accordingly, of the mechanisms involving them in immune cells activation and migration.

LN-Derived Fibroblastic Reticular Cells and Their Impact on T Cell Response—A Systematic Review

“…Severino et al demonstrated previously, in 2017, the increased IL-33 gene expression in human FRCs after treatment with IFN-γ or IL-1β and TNF-α. These cytokines are usually released during a course of an immune response, supporting the Aparicio-Domingo et al findings that FRCs are the main source for IL-33 [ 9 ].…”

“…Their ability for cytokine and chemokine production has been demonstrated in several studies [ 2 , 5 , 6 ], and their relevant multifunctional roles and multiple subsets have been previously defined [ 7 ]. In addition, mice and human lymph node-derived FRC’s ability to react to inflammatory stimuli has been described [ 8 , 9 , 10 ].…”

Repetitive ischemic injuries to the kidneys result in lymph node fibrosis and impaired healing

“…FRCs play a critical role in the trafficking of naive T cells into the LN by secreting chemokines, such as CCL19 and CCL21 (16)(17)(18)(19)(20)(21). In addition, FRCs produce a highly organized interconnected framework of extracellular matrix (ECM) fibers, generating conduits for the movement of antigens and immune cells within the LN (11, The contribution of the kidney-draining lymph node (KLN) to the pathogenesis of ischemiareperfusion injury (IRI) of the kidney and its subsequent recovery has not been explored in depth.…”

Lymph node stromal cells: subsets and functions in health and disease

“…This study concludes that human FRCs can also affect innate and adaptive immune responses [56]. Moreover, microarray analysis of in vitro expanded human FRCs and CD31 − PDPN − DN cells stimulated with either IFN-γ, tumor necrosis factor (TNF)-α plus IL-β, or poly(I:C) revealed the upregulation of a variety of chemokine genes (e.g., CCL2, CCL8, CCL13) as well as the upregulation of HLA class II genes [57], further supporting the putative role of FRCs in coordinating immune cell responses during inflammation [57] . Type 1 IFN dynamically regulated the expression of PD-L1 in LECs, which in turn regulated the expansion, contraction, and survival of these cells in the LN [58].…”