AbstractAstrocyte‐microglia crosstalk is vital for neuronal survival and clearing aggregate accumulation in neurodegenerative diseases. While interleukin‐3 (IL‐3) has been reported to exert both protective and detrimental effects in neurodegenerative diseases, however, its role in α‐synuclein pathology remains unclear. In this study, it is found that astrocytic IL‐3 and microglial IL‐3R are positively responsive to α‐synuclein pathology in the brains of transgenic A53T Parkinson's disease (PD) mice and in an adeno‐associated virus (AAV)‐human α‐synuclein (AAV‐hα‐Syn)‐injected PD mouse model. Exogenous IL‐3 infusion reduces behavioral abnormities and nigrostriatal α‐synuclein pathology. Mechanistically, IL‐3 induces microglial phagocytosis of pathological α‐synuclein while simultaneously stimulating dopaminergic (DA) neurons to clear pathological α‐synuclein via induction of autophagy through the IFN‐β/Irgm1 pathway. Due to its limited efficiency in crossing the blood–brain barrier, a precise IL‐3 delivery strategy is developed by cross‐linking IL‐3 and RVG29 with PEG‐Linker (RVG‐modified IL‐3 nanogels—RVG‐IL3 NGs). Intravenous administration of RVG‐IL3 NGs shows efficient uptake by microglia and DA neurons within the brain. RVG‐IL3 NGs ameliorate motor deficits and pathological α‐synuclein by improving microglial and neuronal function in the AAV‐hα‐Syn mouse model of PD. Collectively, IL‐3 may represent a feasible therapeutic strategy for PD.

2024-09-21·Expert Opinion on Pharmacotherapy

Update on the pharmacological treatment of chronic obstructive pulmonary disease

Review

作者: Albertson, Timothy E. ; Jacques, Madeleine R. ; Kuhn, Brooks T.

INTRODUCTIONChronic obstructive pulmonary disease (COPD) is a common syndrome associated with smoking and environmental exposures coupled with genetic susceptibility. Recent major advancements in the treatment of COPD patients have become available.AREAS COVEREDNew data on the role of classic bronchodilators, including short-acting and long-acting beta2-agonists and anti-muscarinic antagonists, in the treatment of COPD patients are discussed. Data promoting a more targeted approach to inhaled and systemic corticosteroid use in COPD are reviewed. Phosphodiesterase (PDE) inhibitors, including the recently approved PDE 3/4 inhibitor inhaled ensifentrine, are noted. Selective use of antibiotics can play a role in complex COPD patients. COPD patients with evidence of asthma-COPD overlap syndrome and type-two lymphocytic inflammatory-mediated airway constriction appear to respond to biologics, particularly the anti-IL-4/IL-3 antagonist monoclonal antibody, dupilumab.EXPERT OPINIONNew therapeutic options have made the approach and treatment of the COPD patient much more complicated. These options tend to be very expensive. Attention to identifying the endotype and phenotype will help direct the pharmacotherapy.

2022-04-01·Journal of Allergy and Clinical Immunology1区 · 医学

Demonstration and implications of IL-3 upregulation of CD25 expression on human mast cells

1区 · 医学

Article

作者: Metcalfe, Dean D ; Yin, Yuzhi ; Bai, Yun ; Olivera, Ana

BACKGROUNDCD25⁺ human mast cells (huMCs) have been reported in patients with monoclonal mast cell diseases and in rare association with inflammation. However, the regulation of CD25 expression on huMCs and the possible biologic consequences remain poorly understood.OBJECTIVEWe sought to identify conditions that would upregulate CD25 expression on huMCs and to explore possible functional implications.METHODShuMCs were cultured from peripheral blood progenitor cells over 6 to 8 weeks. Expression of CD25 was determined by fluorescence-activated cell sorting and soluble CD25 by ELISA. Signal transducer and activator of transcription 5 (STAT5) phosphorylation induced by IL-2 in huMCs, regulatory T (Treg) cells, or in cocultured huMCs and Treg cells was examined by fluorescence-activated cell sorting.RESULTSAddition of IL-3 to CD34⁺ progenitors at the initiation of huMC cultures in the presence of stem cell factor and IL-6 upregulated the expression of CD25 in developing huMCs and resulted in shedding of soluble CD25 into the media. Removal of IL-3 after the first week of culture did not affect subsequent expression of CD25. Furthermore, addition of IL-3 14 days after the initiation of the culture did not induce significant CD25 expression. Treatment with anti-IL-3 antibody or the Janus kinase inhibitor tofacitinib blocked IL-3-induced CD25 upregulation. Binding of IL-2 to CD25⁺ huMCs did not induce STAT5 phosphorylation. However, coincubation of Treg cells with CD25⁺ huMCs pretreated with IL-2 was sufficient to result in STAT5 phosphorylation in Treg cells.CONCLUSIONSIL-3 promotes CD25 expression and shedding by huMCs. Although CD25⁺ huMCs do not respond to IL-2, they bind IL-2 and may act as a reservoir of IL-2 to then activate lymphocytes.

100 项与 SM-401 相关的药物交易

登录后查看更多信息