Activation of fibroblastic reticular cells in kidney lymph node during crescentic glomerulonephritis

Abstract

C rescentic glomerulonephritis (GN) is a rapidly progressive inflammatory condition affecting the kidneys that can lead to renal failure in humans within days. 1,2 If left untreated, the majority of patients with crescentic GN will die or become dialysis-dependent within 6 months. 3 The central role of CD4 þ T cell-mediated renal injury in nephrotoxic serum nephritis (NTN), a classic experimental anti-glomerular basement membrane antibody-mediated model of crescentic GN, has been well established. 4-10 Several previous studies have elucidated the role of fibroblastic reticular cells (FRCs), the prominent cells that comprise the stromal compartment of the lymph node (LN), in the activation of an immune response. 11-18 FRCs express the membrane glycoprotein podoplanin (PDPN), but they do not express the leukocyte marker CD45 or the vascular marker CD31, a unique cellular signature in the LN. 15 FRCs secrete the chemokines CCL19, CCL21, and CXCL12, which promote the trafficking of naïve T cells into the LN through specialized vasculature known as high endothelial venules (HEVs). 14 FRCs also maintain the integrity of HEVs through interactions between PDPN on the FRCs and C-type lectin-like receptor 2 on platelets. 19 The chemokines secreted by FRCs contain the newly arrived T cells within the paracortex (T-cell zone) of the LN, where the FRCs provide conduits on which these naïve T cells and antigen-presenting cells migrate and interact, resulting in activation of the T cells. 14 Though the kidney has been proven to be a site of recruitment for activated CD4 þ T helper 1 (Th1) and Th17 cells via expression of chemokines such as CCL20 and CXCL9, 10 the role of the kidney lymph node (KLN) as a secondary lymphoid organ where these T cells are also activated in NTN has not yet been explored in depth. 20 CD4 þ T cells are activated in the spleen during NTN, 10 but splenectomy does not affect kidney damage significantly in these mice. 21 This finding raises the hypothesis that the KLN may be the key secondary lymphoid organ responsible for propagation of the immune response in NTN. The objectives of this study are to explore the phenotypic changes that occur to FRCs in the KLN during the early stages of the immune response and examine the effects that modulation of the activity of FRCs has on kidney damage in NTN.

Role of lymph node stroma and microenvironment in T cell tolerance

“…27 This phenomenon also correlates with the expansion of blood and lymphatic vasculature, likely under the influence of VEGF secretion by FRCs. 30 The expression of the FRC-secreted chemokines CCL19 and CCL21 increases during the early phase of the adaptive immune response to crescentic glomerulonephritis in mice, and this increase correlated with higher populations of CD4 + effector memory T cells and Th17 cells in the kidney-draining LN. 30 Interestingly, the expansion of HEVs also appears to be dependent on LTβR during this phase of the immune response, 31 and these vessels are reinforced by ECM fibers produced by FRCs.…”

“…30 The expression of the FRC-secreted chemokines CCL19 and CCL21 increases during the early phase of the adaptive immune response to crescentic glomerulonephritis in mice, and this increase correlated with higher populations of CD4 + effector memory T cells and Th17 cells in the kidney-draining LN. 30 Although the importance of FRCs to the propagation of the adaptive immune response has been established, increasing evidence now indicates that they also contribute to the innate immune response in the LN. 32 FRCs have the ability to sense the presence of a virus directly via the expression of pattern recognition receptors like TLR7, which recognizes intracellular viral RNA, resulting in the production of pro-inflammatory cytokines, such as TNF, CCL2, and IL-6.…”

“…[23][24][25][26][27][28][29] In the early phase of the immune response, FRCs undergo LTβRdependent proliferation, which results in the expansion of the LN, allowing for influx of lymphocytes and antigen-presenting cells. 30 Interestingly, the expansion of HEVs also appears to be dependent on LTβR during this phase of the immune response, 31 and these vessels are reinforced by ECM fibers produced by FRCs. 27 Katakai et al demonstrated that LTβR signaling induced the formation of extracellular matrix (ECM) meshwork by LN SCs in vitro, 26 and this increase in ECM production has been observed in the kidney-draining LNs of mice during the early phase of crescentic glomerulonephritis in vivo as well.…”

“…30 Interestingly, the expansion of HEVs also appears to be dependent on LTβR during this phase of the immune response, 31 and these vessels are reinforced by ECM fibers produced by FRCs. 30 The expression of the FRC-secreted chemokines CCL19 and CCL21 increases during the early phase of the adaptive immune response to crescentic glomerulonephritis in mice, and this increase correlated with higher populations of CD4 + effector memory T cells and Th17 cells in the kidney-draining LN. 30 Although the importance of FRCs to the propagation of the adaptive immune response has been established, increasing evidence now indicates that they also contribute to the innate immune response in the LN.…”

“…27 Katakai et al demonstrated that LTβR signaling induced the formation of extracellular matrix (ECM) meshwork by LN SCs in vitro, 26 and this increase in ECM production has been observed in the kidney-draining LNs of mice during the early phase of crescentic glomerulonephritis in vivo as well. 30 Although the importance of FRCs to the propagation of the adaptive immune response has been established, increasing evidence now indicates that they also contribute to the innate immune response in the LN. 30 The expression of the FRC-secreted chemokines CCL19 and CCL21 increases during the early phase of the adaptive immune response to crescentic glomerulonephritis in mice, and this increase correlated with higher populations of CD4 + effector memory T cells and Th17 cells in the kidney-draining LN.…”