In secondary lymphoid organs, development and homeostasis of stromal cells such as podoplanin (Pdpn)-positive fibroblastic reticular cells (FRCs) are regulated by hematopoietic cells, but the cellular and molecular mechanisms of such regulation have remained unclear. Here we show that ablation of either signal regulatory protein α (SIRPα), an Ig superfamily protein, or its ligand CD47 in conventional dendritic cells (cDCs) markedly reduced the number of CD4 cDCs as well as that of Pdpn FRCs and T cells in the adult mouse spleen. Such ablation also impaired the survival of FRCs as well as the production by CD4 cDCs of tumor necrosis factor receptor (TNFR) ligands, including TNF-α, which was shown to promote the proliferation and survival of Pdpn FRCs. CD4 cDCs thus regulate the steady-state homeostasis of FRCs in the adult spleen via the production of TNFR ligands, with the CD47-SIRPα interaction in cDCs likely being indispensable for such regulation.

Signal regulatory protein a (SIRPa), an immunoglobulin superfamily protein that is expressed predominantly in myeloid lineage cells such as dendritic cells (DCs) or macrophages, mediates cell-cell signaling. In the immune system, SIRPa is thought to be important for homeostasis of DCs, but it remains unclear whether SIRPa intrinsic to DCs is indeed indispensable for such functional role. Thus, we here generated the mice, in which SIRPa was specifically ablated in CD11c + DCs (Sirpa DDC ). Sirpa DDC mice manifested a marked reduction of CD4 + CD8a -conventional DCs (cDCs) in the secondary lymphoid organs, as well as of Langerhans cells in the epidermis. Such reduction of cDCs in Sirpa DDC mice was comparable to that apparent with the mice, in which SIRPa was systemically ablated. Expression of SIRPa in DCs was well correlated with that of either endothelial cell-selective adhesion molecule (ESAM) or Epstein-Barr virus-induced molecule 2 (EBI2), both of which were also implicated in the regulation of DC homeostasis. Indeed, ESAM + or EBI2 + cDCs were markedly reduced in the spleen of Sirpa DDC mice. Thus, our results suggest that SIRPa intrinsic to CD11c + DCs is essential for homeostasis of cDCs in the secondary lymphoid organs and skin.

Background: The pathogenesis of meningioma in females and its association with exogenous progesterone is remained unclear. This study was aimed to examine expression of Progesterone receptor (PR) and Neurofibromatosis-2 (NF2) and assess their relationships to history of exogenous progesterone use and risk of meningioma.Methods: Our study was a case-control study that involves 115 females, 40 cases who diagnosed with orbito-cranial meningioma and 75 controls of healthy, that has been presented in previous study. The demographic characteristics, reproductive factors, and history of progesterone use were obtained in–depth face-to-face interviews. PR and NF2 mRNA were assessed by real-time quantitative polymerase chain reaction (RT-qPCR) on serum specimens.Results: The mean age of participants in cases vs. controls were 46.6 ± 6.2 vs. 46.5 ± 7.45 (P = 0.969). The expression of PR and NF2 in cases was significantly lower than in controls. The longer duration of progesterone exposure was significantly associated with lower expression of PR and NF2. Significant association between lower expression of PR (OR 11.7; 95% CI 4.17–32.9; P < 0.001 comparing the lowest quartile vs. 3 highest quartile of PR) and NF2 (OR 4.23; 95% CI 1.85–9.67; P = 0.001 comparing the 2 lowest quartiles vs. 2 highest quartiles) with increased risk of meningioma were also reported.Conclusion: In this study we showed that the longer the exposure to exogenous progesterone, the lower the expression of PR and NF2 mRNA in the serum. Low expression of PR and NF2 were associated with higher risk of meningioma, suggesting that low PR expression and inactivation of NF2 might play a key role in progesterone-associated meningioma tumorigenesis and may be potential clinical marker for females at higher risk of meningioma.

Signal regulatory protein α (SIRPα) is expressed predominantly on type 2 conventional dendritic cells (cDC2s) and macrophages. We previously showed that mice systemically lacking SIRPα were resistant to experimental autoimmune encephalomyelitis (EAE). Here, we showed that deletion of SIRPα in CD11c + cells of mice (Sirpa DC mice) also markedly ameliorated the development of EAE. The frequency of cDCs and migratory DCs (mDCs), as well as that of Th17 cells, were significantly reduced in draining lymph nodes of Sirpa DC mice at the onset of EAE. In addition, we found the marked reduction in the number of Th17 cells and DCs in the CNS of Sirpa DC mice at the peak of EAE. Whereas inducible systemic ablation of SIRPα before the induction of EAE prevented disease development, that after EAE onset did not ameliorate the clinical signs of disease. We also found that EAE development was partially attenuated in mice with CD11c + cell-specific ablation of CD47, a ligand of SIRPα. Collectively, our results suggest that SIRPα expressed on CD11c + cells, such as cDC2s and mDCs, is indispensable for the development of EAE, being required for the priming of self-reactive Th17 cells in the periphery as well as for the inflammation in the CNS.