期刊
JOURNAL OF IMMUNOLOGY
卷 202, 期 11, 页码 3187-3197出版社
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1900089
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资金
- National Natural Science Foundation of China [81825010, 81730043, 81621002, 31811540397, 31330027, 91642207]
- National Key Basic Research Grant from the Ministry of Science and Technology of China [2015CB943200]
- National Multiple Sclerosis Society [TA 30 59 -A-2]
- NATIONAL CANCER INSTITUTE [ZIABC011801] Funding Source: NIH RePORTER
Dendritic cells (DCs) play key roles in Ab responses by presenting Ags to lymphocytes and by producing proinflammatory cytokines. In this study, we reported that DC-specific knockout of discs large homologue 1 (Dlg1) resulted in a significantly reduced capacity to mediate Ab responses to both thymus-independent and thymus-dependent Ags in Dlg1(fl/fl)Cd11c-Cre-GFP mice. Mechanistically, Dlg1-deficient DCs showed severely impaired endocytosis and phagocytosis capacities upon Ag exposure. In parallel, loss of Dlg1 significantly jeopardized the proinflammatory cytokine production by DCs upon TLR stimulation. Thus, Dlg1-deficient DCs lost their functions to support innate and adaptive immunities. At a cellular level, Dlg1 exhibited an indispensable function to maintain membrane potential changes by securing potassium ion (K+) efflux and subsequent calcium ion (Ca2+) influx events in DCs upon stimulation, both of which are known to be required for proper function of DCs. At a molecular level, Dlgl did so by retaining the integrity of voltage-gated K+ channels (including Kv1.3) in DCs. The loss of Dlg1 led to a decreased expression of K+ channels, resulting in impaired membrane potential changes and, as a consequence, reduced proinflammatory cytokine production, compromised Ag endocytosis, and phagocytosis. In conclusion, this study provided, to our knowledge, a novel insight into Dlgl and the voltage-gated K+ channels axis in DC functions.
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