scispace - formally typeset
Search or ask a question
Author

Lihui Duan

Other affiliations: Chinese Academy of Sciences
Bio: Lihui Duan is an academic researcher from University of California, San Francisco. The author has contributed to research in topics: Memory B cell & Medicine. The author has an hindex of 4, co-authored 6 publications receiving 139 citations. Previous affiliations of Lihui Duan include Chinese Academy of Sciences.

Papers
More filters
Journal ArticleDOI
10 Oct 2018-Neuron
TL;DR: It is shown that within 2 hr of systemic inflammation, PDGFRβ mural cells of blood vessels rapidly secrete chemokine CCL2, which in turn increases total neuronal excitability by promoting excitatory synaptic transmission in glutamatergic neurons of multiple brain regions.

118 citations

Journal ArticleDOI
TL;DR: It is shown that the transcription factor Hhex interacting with Tle3 promotes memory B cell generation, establishing an important role for Hhex–Tle3 in regulating the transcriptional circuitry governing MBC differentiation.
Abstract: Memory B cells (MBCs) are essential for long-lived humoral immunity However, the transcription factors involved in MBC differentiation are poorly defined Here, using single-cell RNA sequencing analysis, we identified a population of germinal center (GC) B cells in the process of differentiating into MBCs Using an inducible CRISPR-Cas9 screening approach, we identified the hematopoietically expressed homeobox protein Hhex as a transcription factor regulating MBC differentiation The corepressor Tle3 was also identified in the screen and was found to interact with Hhex to promote MBC development Bcl-6 directly repressed Hhex in GC B cells Reciprocally, Hhex-deficient MBCs exhibited increased Bcl6 expression and reduced expression of the Bcl-6 target gene Bcl2 Overexpression of Bcl-2 was able to rescue MBC differentiation in Hhex-deficient cells We also identified Ski as an Hhex-induced transcription factor involved in MBC differentiation These findings establish an important role for Hhex-Tle3 in regulating the transcriptional circuitry governing MBC differentiation

83 citations

Journal ArticleDOI
TL;DR: Local clustering of phosphatidylinositol 3,4-bisphosphate (PI(3,4)P2), a phospholipid with relatively few known signaling functions, is necessary and sufficient for aggregating actin and promoting neuritogenesis and is identified as an important signaling molecule during early development.
Abstract: Neurite initiation is critical for neuronal morphogenesis and early neural circuit development. Recent studies showed that local actin aggregation underneath the cell membrane determined the site of neurite initiation. An immediately arising question is what signaling mechanism initiated actin aggregation. Here we demonstrate that local clustering of phosphatidylinositol 3,4-bisphosphate (PI(3,4)P2), a phospholipid with relatively few known signaling functions, is necessary and sufficient for aggregating actin and promoting neuritogenesis. In contrast, the related and more extensively studied phosphatidylinositol 4,5-bisphosphate or phosphatidylinositol (3,4,5)-trisphosphate (PIP3) molecules did not have such functions. Specifically, we showed that beads coated with PI(3,4)P2 promoted actin aggregation and neurite initiation, while pharmacological interference with PI(3,4)P2 synthesis inhibited both processes. PI(3,4)P2 clustering occurred even when actin aggregation was pharmacologically blocked, demonstrating that PI(3,4)P2 functioned as the upstream signaling molecule. Two enzymes critical for PI(3,4)P2 generation, namely, SH2 domain-containing inositol 5-phosphatase and class II phosphoinositide 3-kinase α, were complementarily and non-redundantly required for actin aggregation and neuritogenesis, as well as for subsequent dendritogenesis. Finally, we demonstrate that neural Wiskott-Aldrich syndrome protein and the Arp2/3 complex functioned downstream of PI(3,4)P2 to mediate neuritogenesis and dendritogenesis. Together, our results identify PI(3,4)P2 as an important signaling molecule during early development and demonstrate its critical role in regulating actin aggregation and neuritogenesis.

31 citations

Journal ArticleDOI
12 Oct 2021-Immunity
TL;DR: In this article, the authors examined the contribution of interleukin (IL)-4 on B cell fate decisions in the germinal centers (GCs) and identified a subset of light zone GC B cells expressing high IL-4 receptor-a (IL4Ra) and CD23 and lacking a Myc-associated signature.

27 citations

Journal ArticleDOI
11 Feb 2022-Science
TL;DR: It is found that type-2 conventional DCs in the spleen depend on Gα13 and adhesion G protein–coupled receptor family member-E5 (Adgre5, or CD97) for positioning in blood-exposed locations and Mechanosensing of red blood cells optimizes the antigen capture and presentation functions of splenic cDC2s.
Abstract: Dendritic cells (DCs) are crucial for initiating adaptive immune responses. However, the factors that control DC positioning and homeostasis are incompletely understood. We found that type-2 conventional DCs (cDC2s) in the spleen depend on Gα13 and adhesion G protein–coupled receptor family member-E5 (Adgre5, or CD97) for positioning in blood-exposed locations. CD97 function required its autoproteolytic cleavage. CD55 is a CD97 ligand, and cDC2 interaction with CD55-expressing red blood cells (RBCs) under shear stress conditions caused extraction of the regulatory CD97 N-terminal fragment. Deficiency in CD55-CD97 signaling led to loss of splenic cDC2s into the circulation and defective lymphocyte responses to blood-borne antigens. Thus, CD97 mechanosensing of RBCs establishes a migration and gene expression program that optimizes the antigen capture and presentation functions of splenic cDC2s. Description CD97 helps DCs fight going with the flow A subset of conventional dendritic cells (DCs) called cDC2s are found within a blood-exposed region of the spleen. These cells efficiently capture antigens from the blood and present them to T cells. However, how cDC2s sense their location regarding blood flow remains unclear. Liu et al. found that in mice, the N-terminal fragment of the G protein–coupled receptor CD97 mechanically senses CD55 expressed on red blood cells. This triggers the Gα13 signaling required for correct cDC2 positioning. Deficiencies in the CD55–CD97–Gα13 pathway result in a loss of cDC2s into the circulation and impaired immune responses to blood-borne bacteria. —STS Mechanosensing of red blood cells optimizes the antigen capture and presentation functions of splenic dendritic cells. INTRODUCTION Antigen capture and presentation by conventional dendritic cells (cDCs) is crucial for the initiation of adaptive immune responses. These responses often take place inside secondary lymphoid organs. The spleen is the largest secondary lymphoid organ, has an open blood circulation, and fosters T cell and antibody responses against blood-borne pathogens. A major population of cDCs within the spleen, called cDC2s, is situated in a blood-exposed location at the interface of the white pulp and the red pulp, known as the bridging channel. These cDC2s are very efficient at capturing antigens from the blood and presenting them to T cells, but the factors that enable cDC2s to sense their location with respect to blood flow are not well understood. RATIONALE G protein–coupled receptors (GPCRs) that signal through Gα13-containing heterotrimeric G proteins can cause chemorepulsion and thereby help to confine cells in tissue niches. Whether these G proteins and associated GPCRs are involved in cDC positioning and function has been unclear. RESULTS Gα13 and the downstream effector ArhGEF1 were required for cDC2 positioning in blood-exposed regions of the mouse spleen. Using in vivo CRISPR-based screening, we identified adhesion GPCR family member E5 (Adgre5, or CD97) as a Gα13-coupled receptor needed for splenic cDC2 positioning. In the absence of Gα13, ArhGEF1, or CD97, there was a deficiency of splenic cDC2s but not cDC1s. Intravital two-photon microscopy and spleen transplant experiments showed that this deficiency reflected a loss of splenic cDC2s into the blood circulation. As a member of the adhesion GPCR family, CD97 has a large extracellular domain and is expressed as a noncovalent heterodimer of the extracellular N-terminal fragment (NTF) and the GPCR domain. The CD97 NTF binds CD55 on other cells. CD97 engagement by CD55 on red blood cells (RBCs) under conditions of shear stress led to the removal of the CD97 NTF and the activation of the CD97 GPCR domain. A mutant form of CD97 that could not undergo autoproteolytic cleavage or NTF extraction was not able to restore the cDC2 compartment of CD97 null mice. Deficiency in the CD55-CD97-Gα13 pathway was associated with a reduced ability to mount T follicular helper cell and antibody responses to modified RBCs and to blood-borne bacteria. CD97-deficient splenic cDC2s had increased F-actin content and markedly altered gene expression. Gene set enrichment analysis suggested that part of the altered gene expression profile was due to increased activity of the G-actin–repressed Mrtf transcription factors. The transcription factor IRF4 is important for cDC2 homeostasis, and CD97 expression in cDC2s was promoted by IRF4. Overexpression of CD97 could partially restore splenic cDC2s in IRF4-deficient mice. CONCLUSION Homeostasis of cDC2s within the spleen depends on CD97 mechanosensing of circulating CD55+ RBCs. This pathway enables cDC2s to sense exposure to blood flow and thereby avoid loss into the blood circulation. We speculate that by leading to activation of Rho, CD97 signaling causes the cell to retract membrane processes from flow-exposed locations. Rho signaling may also enhance integrin-mediated adhesion of cDC2s within the spleen. CD97 signaling allows cDC2s to position at the tissue-blood interface, a location that optimizes antigen capture and enables very rapid immune responses to systemic pathogens. CD97 is widely expressed in the immune system and other tissues, including some tumors and inflamed tissues, and may allow additional cell types to sense their location on the basis of interactions with CD55+ cells under conditions of fluid flow. CD97 mechanosensing of CD55+ RBCs enables splenic cDC2s to position near blood flow. The spleen is a highly vascularized organ. In a cross-sectional view, B cell follicles (F) and T cell zones (T) highlight white-pulp cords that are separated from the red pulp (RP) by cDC2-containing bridging channels (BC; dashed box). Intravenously administered antibody to CD11c labels blood-exposed cDC (labeled cDC2 appear white). Splenic cDC2s in bridging channels are near open-ended terminal arterioles and are exposed to RBCs as they pass into the red pulp. cDC2s express CD97, and the interaction with CD55 on RBCs exerts a pulling force on CD97, causing extraction of the NTF and activation of the GPCR domain. This pathway promotes the retention of blood-exposed cDC2s in the spleen. i.v., intravenous; GPS, GPCR proteolysis site.

26 citations


Cited by
More filters
Journal ArticleDOI
TL;DR: Emerging evidence for an interaction between Aβ and tau during Alzheimer’s disease (AD) progression that challenges the classical linear trajectory model and offers a new perspective on AD pathophysiology and therapy is reviewed.
Abstract: Patients with Alzheimer's disease (AD) present with both extracellular amyloid-β (Aβ) plaques and intracellular tau-containing neurofibrillary tangles in the brain. For many years, the prevailing view of AD pathogenesis has been that changes in Aβ precipitate the disease process and initiate a deleterious cascade involving tau pathology and neurodegeneration. Beyond this 'triggering' function, it has been typically presumed that Aβ and tau act independently and in the absence of specific interaction. However, accumulating evidence now suggests otherwise and contends that both pathologies have synergistic effects. This could not only help explain negative results from anti-Aβ clinical trials but also suggest that trials directed solely at tau may need to be reconsidered. Here, drawing from extensive human and disease model data, we highlight the latest evidence base pertaining to the complex Aβ-tau interaction and underscore its crucial importance to elucidating disease pathogenesis and the design of next-generation AD therapeutic trials.

460 citations

Journal Article
TL;DR: This review summarizes the five currently best understood signaling pathways implicated in mural cell biology and discusses PDGFB/PDGFRβ- dependent pericyte recruitment, as well as the role of angiopoietins an...
Abstract: Mural cells are essential components of blood vessels and are necessary for normal development, homeostasis, and organ function. Alterations in mural cell density or the stable attachment of mural cells to the endothelium is associated with several human diseases such as diabetic retinopathy, venous malformation, and hereditary stroke. In addition mural cells are implicated in regulating tumor growth and have thus been suggested as potential antiangiogenic targets in tumor therapy. In recent years our knowledge of mural cell function and endothelial-mural cell signaling has increased dramatically, and we now begin to understand the mechanistic basis of the key signaling pathways involved. This is mainly thanks to sophisticated in vivo experiments using a broad repertoire of genetic technologies. In this review, we summarize the five currently best understood signaling pathways implicated in mural cell biology. We discuss PDGFB/PDGFRβ- dependent pericyte recruitment, as well as the role of angiopoietins an...

229 citations

Journal Article
TL;DR: It is shown that the GC response undergoes a temporal switch in its output as it matures, revealing that the reaction engenders both MBC subsets with different immune effector function and, ultimately, LLPCs at largely separate points in time.
Abstract: Though memory B cells (MBCs) and long-lived plasma cells (LLPCs) are both thought to derive from the germinal center (GC) reaction, there is little insight into or agreement about the signals that control differentiation to one cell type or another. By performing BrdU pulse-labeling studies, GC disruption experiments and V gene sequencing, we found that the generation of these cell types is actually temporally controlled and separated during the immune response. We report that MBCs mainly derive from early GCs (much before GC peak size), while more affinity matured LLPCs are predominantly formed during late GCs - long after its peak in size. Based on these findings, we propose a new model that the GC response undergoes a temporal switch, functioning quite differently at early and late stages. Therefore the generation of MBCs and LLPCs is the consequence of a general shift in GC output over time rather than the result of specific instructive signals that are selectively delivered to GC B cells at any given time during the response. We also present direct evidence that a large fraction of long-lived IgM+ MBC, and even some IgG+ MBC, are formed at very early time points, prior to the existence of detectable GCs. The knowledge of when specific long-lived immune-effector cells are generated during an immune response has strong implications for vaccine design and understanding long-term pathogen immunity.

228 citations

Journal ArticleDOI
TL;DR: It is proposed that gut microbiota regulates pain in the peripheral and central nervous system, and targeting gut microbiota by diet and pharmabiotic intervention may represent a new therapeutic strategy for the management of chronic pain.
Abstract: Summary The relationship between gut microbiota and neurological diseases, including chronic pain, has received increasing attention. The gut microbiome is a crucial modulator of visceral pain, whereas recent evidence suggests that gut microbiota may also play a critical role in many other types of chronic pain, including inflammatory pain, headache, neuropathic pain, and opioid tolerance. We present a narrative review of the current understanding on the role of gut microbiota in pain regulation and discuss the possibility of targeting gut microbiota for the management of chronic pain. Numerous signalling molecules derived from gut microbiota, such as by-products of microbiota, metabolites, neurotransmitters, and neuromodulators, act on their receptors and remarkably regulate the peripheral and central sensitisation, which in turn mediate the development of chronic pain. Gut microbiota-derived mediators serve as critical modulators for the induction of peripheral sensitisation, directly or indirectly regulating the excitability of primary nociceptive neurones. In the central nervous system, gut microbiota-derived mediators may regulate neuroinflammation, which involves the activation of cells in the blood–brain barrier, microglia, and infiltrating immune cells, to modulate induction and maintenance of central sensitisation. Thus, we propose that gut microbiota regulates pain in the peripheral and central nervous system, and targeting gut microbiota by diet and pharmabiotic intervention may represent a new therapeutic strategy for the management of chronic pain.

147 citations

Journal ArticleDOI
TL;DR: Germinal centers (GCs) are microanatomical sites of B cell clonal expansion and antibody affinity maturation as discussed by the authors , and B cells undergo the Darwinian process of somatic diversification and affinity-driven selection of immunoglobulins that produces the high-affinity antibodies essential for effective humoral immunity.
Abstract: Germinal centers (GCs) are microanatomical sites of B cell clonal expansion and antibody affinity maturation. Therein, B cells undergo the Darwinian process of somatic diversification and affinity-driven selection of immunoglobulins that produces the high-affinity antibodies essential for effective humoral immunity. Here, we review recent developments in the field of GC biology, primarily as it pertains to GCs induced by infection or immunization. First, we summarize the phenotype and function of the different cell types that compose the GC, focusing on GC B cells. Then, we review the cellular and molecular bases of affinity-dependent selection within the GC and the export of memory and plasma cells. Finally, we present an overview of the emerging field of GC clonal dynamics, focusing on how GC and post-GC selection shapes the diversity of antibodies secreted into serum.

131 citations