Biology subjects

Hegde, S.

Publications and source records attributed to Hegde, S..

At least 37 records · Page 2Linked to original sources

bioRxiv2023

Fibrinogen and complement factor H: The two crucial markers of Parkinson's disease with cognitive impairment

Animal model-assisted validation is vital for biomarker studies. It provides better means for understanding disease pathogenesis and opens avenues for addressing therapeutics. Our earlier non-targeted label free proteomics-based biomarker study on CSF of Parkinsons disease (PD) patients with cognitive impairment (PDCI), revealed the presence of elevated levels of fibrinogen and complement factor H (CFAH) in PDCI-CSF. In the present study, we aimed to determine if these proteins harbor a pathogenic potential, when present above physiological levels. Native fibrinogen and recombinant CFAH were intraperitoneally injected in adult C57BL/6J mice and 48h later, motor and cognitive behavioral deficits as well as their neuroanatomical correlates were noted. The reduction in stride length in fibrinogen and CFAH injected mice indicate shuffling gait, often seen in PD patients. Motor deficit was complemented by the loss of dopaminergic (DA) neurons in SNpc, compensatory hypertrophy of the surviving neurons, and reduction in TH expression in striatum, thus reminiscing PD pathology. The low discrimination index in (novel object recognition) NOR test complemented by morphological alterations in Nissl-stained CA-1 and subiculum neurons in the fibrinogen-injected mice imply recognition memory deficits. Thus, our study provides objective evidence that fibrinogen and CFAH harbor the potential to induce motor deficits and cognitive impairments in mice, akin to the PDCI-associated neuro-pathological deficits, and thus are potential biomarkers.

neuroscience↗

bioRxiv2023

Glutamylation of Npm2 and Nap1 acidic disordered regions increases DNA charge mimicry to enhance chaperone efficiency

Histone chaperones-structurally diverse, non-catalytic proteins enriched with acidic intrinsically disordered regions (IDRs)-protect histones from spurious nucleic acid interactions and guide their deposition into and out of nucleosomes. Despite their conservation and ubiquity, the function of the chaperone acidic IDRs remains unclear. Here, we show that the Xenopus laevis Npm2 and Nap1 acidic IDRs are substrates for TTLL4 (Tubulin Tyrosine Ligase Like 4)-catalyzed post-translational glutamate-glutamylation. We demonstrate that, to bind, stabilize, and deposit histones into nucleosomes, chaperone acidic IDRs function as DNA mimetics. Our biochemical, computational, and biophysical studies reveal that glutamylation of these chaperone polyelectrolyte acidic stretches functions to enhance DNA electrostatic mimicry, promoting the binding and stabilization of H2A/H2B heterodimers and facilitating nucleosome assembly. This discovery provides insights into both the previously unclear function of the acidic IDRs and the regulatory role of post-translational modifications in chromatin dynamics.

biochemistry↗

bioRxiv2023

Single-cell immune multi-omics and repertoire analyses in pancreatic ductal adenocarcinoma reveal differential immunosuppressive mechanisms within different tumour microenvironments

Pancreatic ductal adenocarcinoma (PDAC) has an extremely poor prognosis. Understanding the multiple mechanisms by which the tumour evades immune control, and how these mechanisms may be disrupted is critical to developing targeted immunotherapies. Previous studies have shown that higher lymphocyte infiltration is associated with better survival, and here we investigated what mediates these differences. We performed a comprehensive analysis of PDAC-associated immune cells using single cell multi-omics coupled with re-analysis of public PDAC scRNA-seq datasets. We introduce novel single-cell and repertoire analyses that have uncoupled diverse roles and contributions of various immune cell populations within different tumour microenvironments (TMEs). They revealed clear distinctions in the clonal characteristics among different patient groups, provided valuable insights into the mechanisms of immune cell migration and tissue adaptation underlying these disparities. These results point to differential CD4 polarisation of intra-tumoural T cells, differential B cell differentiation, GC reactions, antigen presentation pathways, and distinct cell-cell communication between the myeloid-enriched and adaptive-enriched groups. Overall, we identified two major distinct themes for future immune intervention within PDAC patients between those with higher adaptive versus myeloid immune cell infiltration.

immunology↗

bioRxiv2023

Interkingdom interactions shape the fungal microbiome of mosquitoes

The mosquito microbiome is an important modulator of vector competence and vectoral capacity. Unlike the extensively studied bacterial microbiome, fungal communities in the mosquito microbiome (mycobiome) remain largely unexplored. To work towards getting an improved understanding of the fungi associated with mosquitoes, we sequenced the mycobiome of three field-collected and laboratory-reared mosquito species (Aedes albopictus, Aedes aegypti, and Culex quinquefasciatus). Our analysis showed both environment and host species were contributing to the diversity of the fungal microbiome of mosquitoes. When comparing species, Ae. albopictus possessed a higher number of diverse fungal taxa than Cx. quinquefasciatus, while strikingly less than 1% of reads from Ae. aegypti samples were fungal. Fungal reads from Ae. aegypti were <1% even after inhibiting host amplification using a PNA blocker, indicating that this species lacked a significant fungal microbiome that was amplified using this sequencing approach. Using a mono-association mosquito infection model, we confirmed that mosquito-derived fungal isolates colonize and for Aedes mosquitoes, support growth and development at comparable rates to their bacterial counterparts. Strikingly, native bacterial taxa isolated from mosquitoes impeded the colonization of symbiotic fungi in Ae. aegypti suggesting interkingdom interactions shape fungal microbiome communities. Collectively, this study adds to our understanding of the fungal microbiome of different mosquito species, that these fungal microbes support growth and development, and highlights that microbial interactions underpin fungal colonization of these medically relevent species.

microbiology↗

bioRxiv2023

microRNA profile of endometrial cancer from Indian patients-Identification of potential biomarkers for prognosis

Endometrial cancer is one of the major cancers in women throughout the world. If diagnosed early, these cancers are treatable and the prognosis is usually good. However, one major problem in treating endometrial cancer is accurate diagnosis and staging. Till date, the choice method for diagnosis and staging is histopathology. Although there are few molecular markers identified, they are not always sufficient in making accurate diagnosis and deciding on therapeutic strategy. As a result, very often patients are under treated or over treated. In this study, our group has profiled microRNAs (miRNA) from Indian patients using NGS-based approach. We have identified differentially expressed microRNAs in endometrial cancer. These microRNAs have also been compared to data from TCGA (The Cancer Genome Atlas), which represent other populations and also correlated to relevance in overall survival. Using in-silico approaches, mRNA targets of the miRNAs have been predicted. After comparing with TCGA, we have identified 16 miRNA-mRNA pairs which could be potential prognostic biomarkers for endometrial cancer. This is the first miRNA profiling report from Indian cohort and one of the very few studies which have identified potential biomarkers of prognosis in endometrial cancer.

cancer biology↗

bioRxiv2023

Chemical-guided SHAPE sequencing (cgSHAPE-seq) informs the binding site of RNA-degrading chimeras targeting SARS-CoV-2 5' untranslated region

One of the hallmarks of RNA viruses is highly structured untranslated regions (UTRs) in their genomes. These conserved RNA structures are often essential for viral replication, transcription, or translation. In this report, we discovered and optimized a new type of coumarin derivatives, such as C30 and C34, which bind to a four-way RNA helix called SL5 in the 5 UTR of the SARS-CoV-2 RNA genome. To locate the binding site, we developed a novel sequencing-based method namely cgSHAPE-seq, in which the acylating chemical probe was directed to crosslink with the 2-OH groups of ribose at the ligand binding site. This crosslinked RNA could then create read-through mutations during reverse transcription (i.e., primer extension) at single-nucleotide resolution to uncover the acylation locations. cgSHAPE-seq unambiguously determined that a bulged G in SL5 was the primary binding site of C30 in the SARS-CoV-2 5 UTR, which was validated through mutagenesis and in vitro binding experiments. C30 was further used as a warhead in RNA-degrading chimeras to reduce viral RNA expression levels. We demonstrated that replacing the acylating moiety in the cgSHAPE probe with ribonuclease L recruiter (RLR) moieties yielded RNA degraders active in the in vitro RNase L degradation assay and SARS-CoV-2 5 UTR expressing cells. We further explored another RLR conjugation site on the E ring of C30/C34 and discovered improved RNA degradation activities in vitro and in cells. The optimized RNA-degrading chimera C64 inhibited live virus replication in lung epithelial carcinoma cells.

biochemistry↗

bioRxiv2023

A dirofilariasis mouse model for heartworm preclinical research

Use of experimental cats and dogs in veterinary heartworm preclinical drug research is increasing. As a potential alternative primary in vivo heartworm preventative drug screen, we assessed lymphopenic mice with ablation of the interleukin-2/7 common gamma chain ({gamma}c) as susceptible to the larval development phase of D. immitis. Non-obese diabetic (NOD) Severe Combined ImmunoDeficient (SCID){gamma}c-/-(NSG / NXG) mice consistently yielded viable D. immitis larvae at 2-4 weeks post-infection across multiple experiments, different batches of infectious larvae inoculates, different isolates of D. immitis and at independent laboratories. Mice did not display any overt clinical signs associated with infection up to 4 weeks. Developing larvae were found in subcutaneous and muscle fascia tissues, the natural site of this stage of heartworm in dogs. Larvae retrieved from NSG / NXG mice were mid-L4 stage of development. Compared with 14-day in vitro propagated larvae, in vivo derived L4 were significantly larger and contained expanded Wolbachia endobacteria titres, determined by QPCR and Fluorescent in situ Hybridisation (FISH). We established an ex vivo 6-day L4 paralytic screening system against nematodicidal agents (moxidectin, levamisole) which highlighted discrepancies in relative drug sensitivities in comparison with in vitro reared L4 D. immitis. We demonstrated effective depletion of Wolbachia by 70-90% in D. immitis L4 following 2-7 day oral in vivo exposures of NSG / NXG infected mice with doxycycline or the rapid-acting investigational anti-Wolbachia drug, AWZ1066S. We validated the NSG / NXG mouse model as a filaricide drug screen by in vivo treatments with single injections of moxidectin, which mediated 60-88% reduction in L4 larvae at 14-28 days. Future adoption of the mouse model as a first-line efficacy screen will benefit end-user laboratories conducting research and development of novel heartworm preventatives via increased access, rapid turnaround and reduced costs whilst simultaneously decreasing need for experimental cat or dog use.

microbiology↗

bioRxiv2023

Aedes aegypti gut transcriptomes respond differently to microbiome transplants from field-caught or laboratory-reared mosquitoes.

The mosquito microbiome is critical for host development and plays a major role in many aspects of mosquito biology. While the microbiome is commonly dominated by a small number of genera, there is considerable variation in composition among mosquito species, life stages, and geography. How the host controls and is affected by this variation is unclear. Using microbiome transplant experiments, we asked whether there were differences in transcriptional responses when mosquitoes of different species were used as microbiome donors. We used microbiomes from four different donor species spanning the phylogenetic breadth of the Culicidae, collected either from the laboratory or field. We found that when recipients received a microbiome from a donor reared in the laboratory, the response was remarkably similar regardless of donor species. However, when the donor had been collected from the field, far more genes were differentially expressed. We also found that while the transplant procedure did have some effect on the host transcriptome, this is likely to have had a limited effect on mosquito fitness. Overall, our results highlight the possibility that variation in mosquito microbiome communities are associated with variability in host-microbiome interactions and further demonstrate the utility of the microbiome transplantation technique.

microbiology↗

bioRxiv2023

Active zone protein SYD-2/Liprin-α acts downstream of LRK-1/LRRK2 to regulate polarized trafficking of synaptic vesicle precursors through clathrin adaptor protein complexes

Synaptic vesicle proteins (SVps) are thought to travel in heterogeneous carriers dependent on the motor UNC-104/KIF1A. In C. elegans neurons, we found that some SVps are transported along with lysosomal proteins by the motor UNC-104/KIF1A. LRK-1/LRRK2 and the clathrin adaptor protein complex AP-3 are critical for the separation of lysosomal proteins from SVp transport carriers. In lrk-1 mutants, both SVp carriers and SVp carriers containing lysosomal proteins are independent of UNC-104, suggesting that LRK-1 plays a key role in ensuring UNC-104-dependent transport of SVps. Additionally, LRK-1 likely acts upstream of the AP-3 complex and regulates the membrane localization of AP-3. The action of AP-3 is necessary for the active zone protein SYD-2/Liprin- to facilitate the transport of SVp carriers. In the absence of the AP-3 complex, SYD-2/Liprin- acts with UNC-104 to instead facilitate the transport of SVp carriers containing lysosomal proteins. We further show that the mistrafficking of SVps into the dendrite in lrk-1 and apb-3 mutants depends on SYD-2, likely by regulating the recruitment of the AP-1/UNC-101. We propose that SYD-2 acts in concert with both the AP-1 and AP-3 complexes to ensure polarized trafficking of SVps.

cell biology↗

bioRxiv2022

Loss of LRP1 in adult neural stem cells impairs migration to ischemic lesions

After ischemia, cells in the brain parenchyma upregulate stromal derived factor 1 (SDF1), driving chemokine receptor CXCR4-mediated migration of adult neural stem cells from the subventricular zone (SVZ) to the ischemic injury. We discovered a novel regulator of CXCR4 in neural stem cells, low-density lipoprotein receptor related protein 1 (LRP1). We employed a tamoxifen-inducible Nestin-Cre to drive expression of a tdTomato reporter and also knockout floxed LRP1 in adult mice and then subjected mice to middle-cerebral artery occlusion. Examination 2 weeks post-stroke reveals a loss of tdTomato positive cells localizing from the SVZ to the lesion. We show that loss of LRP1 disrupts CXCR4-mediated neural stem cell migration in vitro, which is likely driven by LRP1-mediated loss of CXCR4 expression in vivo. Altogether, our results suggest that LRP1 is a novel regulator of CXCR4 in neural stem cells. Highlights- LRP1 KO in adult neural stem cells disrupts migration to ischemic lesions in vivo. - LRP1 KO in adult neural stem cells disrupts migration towards SDF1 in vitro. - LRP1 positively regulates expression of CXCR4 in adult neural stem cells. eTOC blurbAdult neural stem cells can home to ischemic brain injury and are considered an important part of the repair process after stroke. However, little is known about what molecules help drive this response. The authors discovered that LRP1 is a novel regulator of CXCR4, which is essential for neural stem cell migration to ischemic injury.

neuroscience↗

bioRxiv2022

Intratumoral mregDC and CXCL13 T helper niches enable local differentiation of CD8 T cells following PD-1 blockade

Here, we leveraged a large neoadjuvant PD-1 blockade trial in patients with hepatocellular carcinoma (HCC) to search for correlates of response to immune checkpoint blockade (ICB) within T cell-rich tumors. We show that ICB response correlated with the clonal expansion of intratumoral CXCL13+ CH25H+ IL-21+ PD-1+ CD4 T helper cells (CXCL13+ Th) and Granzyme K+ PD-1+ effector-like CD8 T cells, whereas terminally exhausted CD39hi TOXhi PD-1hi CD8 T cells dominated in non-responders. Strikingly, most T cell receptor (TCR) clones that expanded post-treatment were found in pre-treatment biopsies. Notably, PD-1+ TCF-1+ progenitor-like CD8 T cells were present in tumors of responders and non-responders and shared clones mainly with effector-like cells in responders or terminally differentiated cells in non-responders, suggesting that local CD8 T cell differentiation occurs upon ICB. We found that these progenitor CD8 T cells interact with CXCL13+ Th cells within cellular triads around dendritic cells enriched in maturation and regulatory molecules, or "mregDC". Receptor-ligand analysis revealed unique interactions within these triads that may promote the differentiation of progenitor CD8 T cells into effector-like cells upon ICB. These results suggest that discrete intratumoral niches that include mregDC and CXCL13+ Th cells control the differentiation of tumor-specific progenitor CD8 T cell clones in patients treated with ICB.

immunology↗

bioRxiv2022

Vertical and horizontal transmission of cell fusing agent virus in Aedes aegypti

Cell fusing agent virus (CFAV) is an insect specific flavivirus (ISF) found in field and laboratory populations of Aedes aegypti. ISFs have recently demonstrated the ability to block the transmission of arboviruses such as dengue, West Nile and Zika viruses. It is thought that vertical transmission is the main route for ISF infections. This has been observed with CFAV, but there is evidence of horizontal and venereal transmission in other ISFs. Understanding the route of transmission can inform strategies to spread ISFs to wild vector populations as a method of controlling pathogenic arboviruses. We crossed individually reared male and female mosquitoes from both a naturally occurring CFAV-positive Ae. aegypti colony and its negative counterpart to provide information on maternal, paternal, and horizontal transmission. RT-PCR was used to detect CFAV in individual female mosquito pupal exuviae and was 89% sensitive, but only 41% in male mosquito pupal exuviae. This is a possible way to screen individuals for infection without destroying the adults. Female-to-male horizontal transmission was not observed during this study, however there was a 31% transmission rate from mating pairs of CFAV-positive males to negative female mosquitoes. Maternal vertical transmission was observed with a filial infection rate of 93%. The rate of paternal transmission was 85% when the female remained negative, 61% when the female acquired CFAV horizontally, and 76% overall. Maternal and paternal transmission of CFAV could allow the introduction of this virus into wild Ae. aegypti populations through male or female mosquito releases, and thus provides a potential strategy for ISF-derived arbovirus control.

microbiology↗

bioRxiv2022

Symbolic quantitative cognition in wild zebrafish (Danio rerio)

Zebrafish (Danio rerio) constitute an excellent model system to investigate the neural and genetic basis of quantitative cognition We tested the ability of reward quantity discrimination of wild-type zebrafish in an associative learning task. We used an operant conditioning paradigm in which the number of horizontal lines zebrafish approached in a 2-alternative forced choice task predicted the number of food reward pellets they would receive. Zebrafish did not learn a preference for the 2-line stimulus predictive of receiving 2 food pellets. However, a subset of the fish performed significantly above chance in a discrimination task with the same apparatus, in which the 2-line stimulus was associated with the same reward but the choice of the 1-line stimulus was not rewarded. Zebrafish also showed a population level learning in a simpler spatial association task with the same apparatus. We also explored the explanatory value of alternative spatial learning hypotheses such as a Win-Stay, Lose-Shift (WSLS) strategy at the individual level for fish in navigating these spatially randomised tasks.

animal behavior and cognition↗

bioRxiv2021

Inter-species microbiota transplantation recapitulates microbial acquisition and persistence in mosquitoes

BackgroundMosquitoes harbor microbial communities that play important roles in their growth, survival, reproduction, and ability to transmit human pathogens. Microbiome transplantation approaches are often used to study host-microbe interactions and identify microbial taxa and assemblages associated with health or disease. However, no such approaches have been developed to manipulate the microbiota of mosquitoes. ResultsHere, we developed an approach to transfer entire microbial communities between mosquito cohorts. We undertook transfers between (Culex quinquefasciatus to Aedes aegypti) and within (Ae. aegypti to Ae. aegypti) species to validate the approach and determine the number of mosquitoes required to prepare donor microbiota. After the transfer, we monitored mosquito development and microbiota dynamics throughout the life cycle. Typical holometabolous lifestyle-related microbiota structures were observed, with higher dynamics of microbial structures in larval stages, including the larval water, and less diversity in adults. Microbiota diversity in recipient adults was also more similar to the microbiota diversity in donor adults. ConclusionsThis study provides the first evidence for successful microbiome transplantation in mosquitoes. Our results highlight the value of such methods for studying mosquito-microbe interactions and lay the foundation for future studies to elucidate the factors underlying microbiota acquisition, assembly, and function in mosquitoes under controlled conditions.

microbiology↗

bioRxiv2021

SUMOylation of Dorsal attenuates Toll/NF-κB signalling

In Drosophila, Toll/NF-{kappa}B signalling plays key roles in both animal development and in host defence. The activation, intensity and kinetics of Toll signalling is regulated by post-translational modifications such as phosphorylation, SUMOylation or ubiquitination that target multiple proteins in the Toll/NF-{kappa}B cascade. Here, we have generated a CRISPR-Cas9 edited Dorsal (DL) variant that is SUMO conjugation resistant (SCR). Intriguingly, embryos laid by dlSCR mothers overcome dl haploinsufficiency and complete the developmental program. This ability appears to be a result of higher transcriptional activation by DLSCR. In contrast, SUMOylation dampens DL transcriptional activation, ultimately conferring robustness to the dorso-ventral program. In the larval immune response, dlSCR animals show increase in crystal cell numbers, stronger activation of humoral defence genes, high cactus levels and cytoplasmic stabilization of DL:Cactus complexes. A mathematical model that evaluates the contribution of the small fraction of SUMOylated DL (<5%) suggests that it acts to block transcriptional activation, driven primarily by DL that is not SUMO conjugated. Our findings define SUMO conjugation as an important regulator of the Toll signalling cascade, in both development and in host defense. Our results broadly indicate that SUMO attenuates DL at the level of transcriptional activation. Further, we hypothesize that SUMO conjugation of DL may be part of a Ubc9 dependant feedback circuit that restrains Toll/NF-{kappa}B signalling.

developmental biology↗

bioRxiv2021

Caspar, an adapter for VAP and TER94, delays the progression of disease by regulating glial inflammation in a Drosophila model of ALS8

Amyotrophic Lateral Sclerosis (ALS) is a fatal, late onset, progressive motor neurodegenerative disorder. We have been studying cellular and molecular mechanisms involved in ALS using a vesicle-associated membrane protein-associated protein B (VAPB/ALS8) Drosophila model, which mimics many systemic aspects of the human disease. Here, we show that the ER resident VAPB interacts with Caspar, an ortholog of human fas associated factor 1 (FAF1). Caspar, in turn, interacts with transitional endoplasmic reticulum ATPase (TER94), a fly ortholog of ALS14 (VCP/p97, Valosin-containing protein), via its UBX domain and poly-ubiqutinated proteins with its UBA domain. Caspar overexpression in the glia extends lifespan and also slows the progression of motor dysfunction in the ALS8 model, a phenomenon that we ascribe to its ability to restrain age-dependant inflammation, modulated by Relish/NF{kappa}B signalling. We hypothesize that Caspar is a key molecule in the pathogenesis of ALS. Caspar connects the plasma membrane (PM) localized immune signalosome to the ER based VAPB degradative machinery, presumably at PM:ER contact sites. The Caspar:TER94:VAPB complex appears to be a strong candidate for regulating both protein homeostasis and NF{kappa}B signalling. These, in turn, regulate glial inflammation and determine progression of disease. Our study projects human FAF1 as an important protein target to alleviate the progression of motor neuron disease.

genetics↗

bioRxiv2021

Fibrinogen and Complement Factor H are promising CSF protein biomarker(s) for Parkinson's disease with cognitive impairment- A Proteomics and ELISA based study

Cognitive impairment is a debilitating non-motor symptom of Parkinsons disease (PD). The diagnosis of PD with cognitive impairment (PDCI) is essentially through clinical and neuropsychological examinations. There is an emerging need to identify biomarker(s) to foresee cognitive decline in PD patients, at an early stage. We performed label-free unbiased nontargeted proteomics (Q-TOF LC/MS-MS) in CSF of non-neurological control (NNC); PDCI; PD and normal pressure hydrocephalus (NPH), followed by targeted ELISA for validation. The diagnosis was confirmed by neuropsychological and MRI assessments prior to CSF collection. Of the 282 proteins identified by mass spectrometry, 42 were differentially altered in PD, PDCI and NPH. Further, 28 proteins were altered in PDCI and 25 in NPH. An interesting overlap of certain proteins was noted both in PDCI and NPH. Five significantly upregulated proteins in PDCI were fibrinogen, gelsolin, complement factor-H, apolipoprotein A-IV and apolipoprotein A-I. Whereas carnosine dipeptidase 1, carboxypeptidase E, dickkpof 3 and secretogranin 3 precursor proteins were down-regulated. NPH also had few uniquely altered proteins viz. insulin-like growth factor-binding protein, ceruloplasmin, -1 antitrypsin, VGF nerve growth factor, neural cell adhesion molecule L1 like protein. Interestingly, the ELISA-derived protein concentrations correlated well with the neuropsychological scores of certain cognitive domains. Executive function was affected both in PDCI and NPH. In PD, Wisconsin card sorting test (WCST) percentile correlated positively with ApoA-IV and negatively with the ratio of ApoAI: ApoA-IV. Thus assessment of a battery of proteins like fibrinogen--chain, CFAH and ApoAI: ApoA-IV ratio alongside neuropsychological could be reliable biomarkers to distinguish PDCI and NPH.

neuroscience↗

bioRxiv2021

Systemic inflammation recruits fast-acting anti-inflammatory innate myeloid progenitors from BM into lymphatics

Innate immune cellular effectors are actively consumed during systemic inflammation but the systemic traffic and the mechanisms that support their replenishment remain unknown. Here we demonstrate that acute systemic inflammation induces the emergent activation of a previously unrecognized system of rapid migration of granulocyte-macrophage progenitors and committed macrophage-dendritic progenitors, but not other progenitors or stem cells, from bone marrow (BM) to lymphatic capillaries. The progenitor traffic to the systemic lymphatic circulation is mediated by Ccl19/Ccr7 and is NF{kappa}B independent, Traf6/I{kappa}B-kinase/SNAP23 activation which is responsible for the secretion of pre-stored Ccl19 by a subpopulation of CD205+/CD172a+ conventional dendritic cells type 2 (cDC2) and upregulation of BM myeloid progenitor Ccr7 signaling. The consequence of this progenitor traffic is anti-inflammatory with promotion of early survival and initiation of replenishment of lymph node cDC.

immunology↗