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01 Single-Cell Analysis of Human Mononuclear Phagocytes Reveals Subset-Defining Markers and Identifies Circulating Inflammatory Dendritic Cells Charles-AntoineDutertre, Etienne Becht, et al. Immunity,2019 In this paper, the authors precisely delineated allmononuclear phagocytes (MNPs) subsets and identified specific markers tounambiguously define cDC2 and monocyte populations via using high-dimensional,single-cell protein and RNA expression analyses of human blood MNPs. Theyreveled that while the commonly used cDC2 and cMo markers (CD1c and CD14,respectively) showed variable expression among cDC2s, several more resolutivemarkers, including FcεRIa and HLA-DQ are the most reliable markers expressed byall cDC2s and CD88 and CD89 restricted to cMos. Among of cDCs, the authorsrevealed that FLT3L-responsive IRF4+CD14+ cDC2 subset accumulates in the bloodof patients with SLE and exhibits pro-inflammatory functions. cDC2s be canfurther divided into two clusters: CD5+ DC2s and CD5+CD163+/-CD14+/- DC3s. Thenthe authors focused on CD14+ DC3s. They further demonstrated that CD14+ DC3sfrom healthy donors had a highly pro-inflammatory secretome triggered by theserum of patients with active SLE. Although CD163+CD14? DC3s were alsoincreased in the patient’s blood, they secreted intermediate quantities ofpro-inflammatory mediators at a higher level than CD5+ DC2s and CD163-CD14-DC3s but at a lower level than inflammatory CD14+ DC3s. Furthermore, cDC2cluster 4, which contained most CD14+ DC3s, was enriched in genes involved inthe role of IL-17A in psoriasis pathway, confirming that in vivo, CD14+ DC3sare programmed to favor Th17 polarization. They also observed that CD14+ DC3shave higher NOTCH2 and lower KLF4 expression compared to all the other cDC2s.The pro-inflammatory nature of CD14+ DC3s was also confirmed by their highexpression of CD354 (TREM1) protein and enrichment in genes involved in theTREM1 signaling pathway. Finally, inflamma- tory CD14+ DC3s were also enrichedin genes from the TWEAK signaling pathway, and TWEAK is one of the multiplepro-inflammatory mediators involved in SLE immunopathology, which these cellssecreted when cultured in the presence of active SLE patients’ serum. https:///10.1016/j.immuni.2019.08.008 02 DifferentialActivation of the Transcription Factor IRF1 Underlies the Distinct ImmuneResponses Elicited by Type I and Type III Interferons AdrianaForero, Snehal Ozarkar, et al. Immunity,2019 Type I and III interferons (IFNs) activatesimilar down- stream signaling cascades, but unlike type I IFNs, type III IFNs(IFNl) do not elicit strong inflammatory responses in vivo. One of the majordifferences observed between type I and III IFNs was the differential inductionof the pro-inflammatory transcription factor IRF1. Type I IFNs, but not typeIII IFNs induced IRF1. Differential IRF1 expression resulted in a distincttranscriptional signature that included induction of IRF1-dependent CXCR3ligands. This suggested a role of IRF1 in the diversification of ISGs that areinducible by type I and III IFNs. And the CXCR3 ligands play an important rolein the recruitment of CXCR3+ cells into sites of inflammation and incoordinating adaptive immune responses. After treatment of IFN-λ, the authors uncovered a gene signature that was consistent with activation of theTAM receptor MERTK. TAM receptors are expressed in macrophages, dendriticcells, and endothelial cells and downregulate the expression of proinflammatorycytokine production following Toll-like receptor (TLR) activation and IFNtreatment. We also identified novel transcription factors, induced by type IIIIFN, involved in cellular proliferation and differentiation suggesting theirrole in maintenance barrier integrity. In a summary, the authors propose thattype III IFNs control viral spread at the site of the infection, restrictingtissue damage by limiting inflammatory responses and initiating epithelialrepair. In contrast, the transient induction of inflammatory responses by typeI IFNs serves to recruit immune effectors to the site of infection to promote protective immunity.ren https:///10.1016/j.immuni.2019.07.007 END |
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來自： 生物_醫(yī)藥_科研 > 《待分類》
