The neurorepellent SLIT2 inhibits LPS-induced proinflammatory signaling in macrophagesSkrtic, Yusuf, Patel
et alJ Immunol (2025) 214 (1), 141-152
Abstract: Macrophages are important mediators of immune responses with critical roles in the recognition and clearance of pathogens, as well as in the resolution of inflammation and wound healing. The neuronal guidance cue SLIT2 has been widely studied for its effects on immune cell functions, most notably directional cell migration. Recently, SLIT2 has been shown to directly enhance bacterial killing by macrophages, but the effects of SLIT2 on inflammatory activation of macrophages are less known. Using RNA sequencing analysis, quantitative polymerase chain reaction, and enzyme-linked immunosorbent assay, we determined that in murine bone marrow-derived macrophages challenged with the potent proinflammatory mediator lipopolysaccharide (LPS), exposure to the bioactive N-terminal fragment of SLIT2 (NSLIT2) suppressed production of proinflammatory cytokines interleukin (IL)-6 and IL-12 and concurrently increased the anti-inflammatory cytokine IL-10. We found that NSLIT2 inhibited LPS-induced MyD88- and TRIF-mediated signaling cascades and did not inhibit LPS-induced internalization of Toll-like receptor 4 (TLR4), but instead inhibited LPS-induced upregulation of macropinocytosis. Inhibition of macropinocytosis in macrophages attenuated LPS-induced production of proinflammatory IL-6 and IL-12 and concurrently enhanced anti-inflammatory IL-10. Taken together, our results indicate that SLIT2 can selectively modulate macrophage response to potent proinflammatory stimuli, such as LPS, by attenuating proinflammatory activation and simultaneously enhancing anti-inflammatory activity. Our results highlight the role of macropinocytosis in proinflammatory activation of macrophages exposed to LPS. Given that LPS-producing bacteria cause host illness through synergistic direct bacterial infection and excessive LPS-induced systemic inflammation, our work suggests a novel therapeutic role for SLIT2 in combatting the significant morbidity and mortality of patients with Gram-negative bacterial sepsis.© The Author(s) 2025. Published by Oxford University Press on behalf of The American Association of Immunologists. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.
MYC regulation of the miR-92-Robo1 axis in Slit-mediated commissural axon guidanceMajumder, Khot, Suriyaarachchi
et alMol Biol Cell (2025) 36 (4), ar50
Abstract: In the developing spinal cord, translational repression of Robo1 expression by microRNA-92 (miR-92) in precrossing commissural axons (CAs) inhibits Slit/Robo1-mediated repulsion facilitating commissural axon projection and midline crossing; however, the regulatory mechanisms governing miR-92 expression in the developing commissural neurons are currently lacking. Here, we propose that the transcription factor MYC regulates miR-92 expression in the developing spinal cord (of either sex) to control Robo1 levels in precrossing CAs, modulating Slit/Robo1-mediated repulsion and midline crossing. MYC, miR-92, and Robo1 are differentially expressed in the developing chicken spinal cord. MYC binds to the promoter region upstream of the gga-miR-92 gene in vitro. MYC knockdown dramatically decreases miR-92 expression and increases chicken Robo1 (cRobo1) levels. In contrast, overexpression of MYC significantly induces miR-92 expression and reduces cRobo1 levels. MYC knockdown or overexpression results in significant inhibition or induction of miR-92 activity in the developing chicken spinal cord, respectively. Disruption of the MYC-dependent regulation of the miR-92-cRobo1 axis affects Slit2-mediated CA growth cone collapse in vitro and impairs CA projection and midline crossing in vivo. These results elucidate the role of the MYC-miR-92-cRobo1 axis in Slit2/Robo1-mediated CA repulsion and midline crossing.
MicroRNA profiling identifies VHL/HIF-2α dependent miR-2355-5p as a key modulator of clear cell Renal cell carcinoma tumor growthPage, Dastous, Richard
et alCancer Cell Int (2025) 25 (1), 71
Abstract: Inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene is one of the first truncal events in clear cell Renal Cell Carcinoma (ccRCC) tumorigenesis. The accumulation of Hypoxia Induced Factor (HIFα) resulting from VHL loss can promote ccRCC tumorigenesis by regulating microRNA (miRNA) expression. Here, we performed miRNA profiling and high-throughput analysis to identify a panel of VHL-dependent miRNAs in ccRCC. Validation of these miRNAs revealed the overexpression of miR-2355-5p in ccRCC cell models and primary tumors. Moreover, we showed a significant increase in circulating miR-2355-5p in plasma from patients with ccRCC. Mechanistically, miR-2355-5p overexpression was confirmed to be HIF-2α dependent. Targeting miR-2355-5p with the CRISPR/Cas9 system not only negatively disrupted the ability of ccRCC cells to stimulate angiogenesis but also decreased cell proliferation and drastically reduced tumor growth in mouse xenograft models. Finally, a miR-2355-5p pulldown assay identified five tumor suppressor genes, ACO1, BTG2, CMTM4, SLIT2, and WDFY2, as potential targets. All five genes were significantly downregulated in ccRCC tumors and mouse xenograft tumors. The results from this research demonstrate the oncogenic ability of miR-2355-5p and shed light on the possible mechanism by which this miRNA controls angiogenesis and tumor growth in VHL-deficient ccRCC.© 2025. The Author(s).
Efficacy and mechanism of the XPO1 inhibitor selinexor combined with decitabine in T-cell lymphoblastic lymphomaMeng, Feng, Zhang
et alAnn Hematol (2025)
Abstract: T-cell lymphoblastic lymphoma (T-LBL) has a poor response to traditional chemotherapy regimens, and is prone to relapse after treatment. Effective drugs are lacking for relapsed and refractory (RR) T-LBL patients, highlighting the need for novel treatments. Selinexor and decitabine have good effects on a variety of hematolymphatic diseases and solid tumors, but how effective they are in treating T-LBL has not been reported. In this study, we first investigated the efficacy and mechanism of selinexor combined with decitabine in the treatment of T- LBL.The proliferation, apoptosis, and cell cycle progression of T-LBL cells were detected via CCK-8 and flow cytometry. Changes in mRNA expression and protein levels were assessed via mRNA sequencing, quantitative real-time PCR, and Western blotting. SLIT2 expression was detected by immunohistochemistry and Western blotting. Tumor xenograft models were established to evaluate the efficacy of drugs in vivo.Selinexor or decitabine alone inhibited T-LBL cell proliferation in a dose-dependent manner. Cotreatment with both drugs had obvious synergistic effects, promoted cell apoptosis, and induced G0/G1-phase cell cycle arrest in T-LBL cells, and the RNA sequencing results indicated that the tumor suppressor gene SLIT2 might be involved in the synergistic effect of the two drugs. In vivo, this combination showed synergistic antitumor effects in xenograft mouse models.In summary, selinexor in combination with decitabine has significant synergistic effects both in vitro and in vivo and represents a new treatment option for RR T-LBL.© 2025. The Author(s).
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