Relish plays a dynamic role in the niche to modulate Drosophila blood progenitor homeostasis in development and infection

Immune challenges demand the gearing up of basal hematopoiesis to combat infection. Little is known about how during development, this switch is achieved to take care of the insult. Here, we show that the hematopoietic niche of the larval lymph gland of Drosophila senses immune challenge and reacts to it quickly through the nuclear factor-κB (NF-κB), Relish, a component of the immune deficiency (Imd) pathway. During development, Relish is triggered by ecdysone signaling in the hematopoietic niche to maintain the blood progenitors. Loss of Relish causes an alteration in the cytoskeletal architecture of the niche cells in a Jun Kinase dependent manner, resulting in the trapping of Hh implicated in progenitor maintenance. Notably, during infection, downregulation of Relish in the niche tilts the maintenance program towards precocious differentiation, thereby bolstering the cellular arm of the immune response.

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Relish plays a dynamic role in the niche to modulate Drosophila blood progenitor homeostasis in development and infection.

10.1101/2021.04.04.438424 ◽

2021 ◽

Author(s):

Parvathy Ramesh ◽

Nidhi Sharma Dey ◽

Aditya Kanwal ◽

Sudip Mandal ◽

Lolitika Mandal

Keyword(s):

Nuclear Factor Κb ◽

Dependent Manner ◽

Immune Challenge ◽

Jun Kinase ◽

Imd Pathway ◽

Maintenance Program ◽

Immune Challenges ◽

Progenitor Maintenance ◽

Ecdysone Signaling ◽

Hematopoietic Niche

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Differential activation of JAK-STAT signaling reveals functional compartmentalization in Drosophila blood progenitors

eLife ◽

10.7554/elife.61409 ◽

2021 ◽

Vol 10 ◽

Author(s):

Diana Rodrigues ◽

Yoan Renaud ◽

K VijayRaghavan ◽

Lucas Waltzer ◽

Maneesha S Inamdar

Keyword(s):

Molecular Genetic ◽

Anterior Lobe ◽

Lymph Gland ◽

Dependent Manner ◽

Immune Challenge ◽

Depth Analysis ◽

Stat Signaling ◽

Stem And Progenitor Cells ◽

Progenitor Maintenance

Blood cells arise from diverse pools of stem and progenitor cells. Understanding progenitor heterogeneity is a major challenge. The Drosophila larval lymph gland is a well-studied model to understand blood progenitor maintenance and recapitulates several aspects of vertebrate hematopoiesis. However in-depth analysis has focused on the anterior lobe progenitors (AP), ignoring the posterior progenitors (PP) from the posterior lobes. Using in situ expression mapping, developmental and transcriptome analysis we reveal PP heterogeneity and identify molecular-genetic tools to study this abundant progenitor population. Functional analysis shows that PP resist differentiation upon immune challenge, in a JAK-STAT-dependent manner. Upon wasp parasitism, AP downregulate JAK-STAT signaling and form lamellocytes. In contrast, we show that PP activate STAT92E and remain undifferentiated, promoting survival. Stat92E knockdown or genetically reducing JAK-STAT signaling permits PP lamellocyte differentiation. We discuss how heterogeneity and compartmentalization allow functional segregation in response to systemic cues and could be widely applicable.

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Differential activation of JAK-STAT signaling in blood cell progenitors reveals functional compartmentalization of the Drosophila lymph gland

10.1101/2020.07.26.219717 ◽

2020 ◽

Author(s):

Diana Rodrigues ◽

Yoan Renaud ◽

K. VijayRaghavan ◽

Lucas Waltzer ◽

Maneesha S. Inamdar

Keyword(s):

Blood Cells ◽

Molecular Genetic ◽

Lymph Gland ◽

Dependent Manner ◽

Immune Challenge ◽

Depth Analysis ◽

Stat Signaling ◽

Stem And Progenitor Cells ◽

Progenitor Maintenance

AbstractBlood cells arise from diverse pools of stem and progenitor cells. Understanding progenitor heterogeneity is a major challenge. The Drosophila larval lymph gland is a well-studied model to understand blood progenitor maintenance and recapitulates several aspects of vertebrate hematopoiesis. However in-depth analysis has focused on progenitors located in lymph gland anterior lobes (AP), ignoring the progenitors from the posterior lobes (PP). Using in situ expression mapping and transcriptome analysis we reveal PP heterogeneity and identify molecular-genetic tools to study this abundant progenitor population. Functional analysis shows that PP resist differentiation upon immune challenge, in a JAK-STAT-dependent manner. Upon wasp parasitism, AP downregulate JAK-STAT signaling and form lamellocytes. In contrast, we show that PP activate STAT92E and remain undifferentiated. Stat92E knockdown in PP or genetically reducing JAK-STAT signaling permits PP lamellocyte differentiation. We discuss how heterogeneity and compartmentalization allow functional segregation in response to systemic cues and could be widely applicable.HighlightsWe provide an in situ and transcriptome map of larval blood progenitors Posterior lymph gland progenitors are refractory to immune challenge STAT activation after wasp parasitism maintains posterior progenitors

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Activation of Nuclear Factor κB and Induction of Inducible Nitric Oxide Synthase by Ureaplasma urealyticumin Macrophages

Infection and Immunity ◽

10.1128/iai.68.12.7087-7093.2000 ◽

2000 ◽

Vol 68 (12) ◽

pp. 7087-7093 ◽

Cited By ~ 28

Author(s):

Y.-H. Li ◽

Z.-Q. Yan ◽

J. Skov Jensen ◽

K. Tullus ◽

A. Brauner

Keyword(s):

Nitric Oxide ◽

Nitric Oxide Synthase ◽

Inducible Nitric Oxide Synthase ◽

Alveolar Macrophages ◽

Nuclear Factor Κb ◽

Inos Expression ◽

Dependent Manner ◽

Nuclear Factor ◽

Oxide Synthase ◽

Inducible Nitric Oxide

ABSTRACT Chronic lung disease (CLD) of prematurity is an inflammatory disease with a multifactorial etiology. The importance ofUreaplasma urealyticum in the development of CLD is debated, and steroids produce some improvement in neonates with this disease. In the present study, the capability of U. urealyticum to stimulate rat alveolar macrophages to produce nitric oxide (NO), express inducible nitric oxide synthase (iNOS), and activate nuclear factor κB (NF-κB) in vitro was characterized. The effect of NO on the growth of U. urealyticum was also investigated. In addition, the impact of dexamethasone and budesonide on these processes was examined. We found that U. urealyticum antigen (≥4 × 107 color-changing units/ml) stimulated alveolar macrophages to produce NO in a dose- and time-dependent manner (P < 0.05). This effect was further enhanced by gamma interferon (100 IU/ml; P < 0.05) but was attenuated by budesonide and dexamethasone (10−4 to 10−6 M) (P < 0.05). The mRNA and protein levels of iNOS were also induced in response to U. urealyticum and inhibited by steroids.U. urealyticum antigen triggered NF-κB activation, a possible mechanism for the induced iNOS expression, which also was inhibited by steroids. NO induced by U. urealyticum caused a sixfold reduction of its own growth after infection for 10 h. Our findings imply that U. urealyticum may be an important factor in the development of CLD. The host defense response againstU. urealyticum infection may also be influenced by NO. The down-regulatory effect of steroids on NF-κB activation, iNOS expression, and NO production might partly explain the beneficial effect of steroids in neonates with CLD.

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Phosphothreonine Lyase Promotes p65 Degradation in a Mitogen-Activated Protein Kinase/Mitogen- and Stress-Activated Protein Kinase 1-Dependent Manner

Infection and Immunity ◽

10.1128/iai.00508-18 ◽

2018 ◽

Vol 87 (1) ◽

Cited By ~ 1

Author(s):

Mingyu Hou ◽

Wenhui Wang ◽

Feizi Hu ◽

Yuanxing Zhang ◽

Dahai Yang ◽

...

Keyword(s):

Protein Kinase ◽

Pathogenic Bacteria ◽

Critical Role ◽

Nuclear Factor Κb ◽

Mapk Signaling ◽

Mitogen Activated Protein Kinase ◽

Dependent Manner ◽

Content Type ◽

Catalytic Active Site ◽

Mitogen Activated Protein

ABSTRACT Bacterial phosphothreonine lyases have been identified to be type III secretion system (T3SS) effectors that irreversibly dephosphorylate host mitogen-activated protein kinase (MAPK) signaling to promote infection. However, the effects of phosphothreonine lyase on nuclear factor κB (NF-κB) signaling remain largely unknown. In this study, we detected significant phosphothreonine lyase-dependent p65 degradation during Edwardsiella piscicida infection in macrophages, and this degradative effect was blocked by the protease inhibitor MG132. Further analysis revealed that phosphothreonine lyase promotes the dephosphorylation and ubiquitination of p65 by inhibiting the phosphorylation of mitogen- and stress-activated protein kinase-1 (MSK1) and by inhibiting the phosphorylation of extracellular signal-related kinase 1/2 (ERK1/2), p38α, and c-Jun N-terminal kinase (JNK). Moreover, we revealed that the catalytic active site of phosphothreonine lyase plays a critical role in regulating the MAPK-MSK1-p65 signaling axis. Collectively, the mechanism described here expands our understanding of the pathogenic effector in not only regulating MAPK signaling but also regulating p65. These findings uncover a new mechanism by which pathogenic bacteria overcome host innate immunity to promote pathogenesis.

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Anti-Inflammatory Activities of Compounds Isolated from the Rhizome of Anemarrhena asphodeloides

Molecules ◽

10.3390/molecules23102631 ◽

2018 ◽

Vol 23 (10) ◽

pp. 2631 ◽

Cited By ~ 7

Author(s):

Zeyuan Wang ◽

Jianfeng Cai ◽

Qing Fu ◽

Lingping Cheng ◽

Lehao Wu ◽

...

Keyword(s):

Nuclear Factor Κb ◽

Microglial Cells ◽

No Production ◽

Dependent Manner ◽

Platycodin D ◽

Protein Levels ◽

Chemical Structures ◽

Ic50 Values ◽

Anti Inflammatory ◽

Anemarrhena Asphodeloides

Fifteen unreported compounds in Anemarrhena asphodeloides, iriflophene (3), hostaplantagineoside C (7), tuberoside G (8), spicatoside B (9), platycodin D (14), platycoside A (15), platycodin D2 (16), polygalacin D2 (17), platycodin D3 (18), isovitexin (20), vitexin (21), 3,4-dihydroxyallylbenzene-3-O-α-l-rhamnopyranosyl(1→6)-β-d-glucopyranoside (22), iryptophan (24), adenosine (25), α-d-Glucose monoallyl ether (26), together with eleven known compounds (1, 2, 4–6, 10–13, 19 and 23), were isolated from the rhizomes of Anemarrhena asphodeloides. The chemical structures of these compounds were characterized using HRMS and NMR. The anti-inflammatory activities of the compounds were evaluated by investigating their ability to inhibit LPS-induced NO production in N9 microglial cells. Timosaponin BIII (TBIII) and trans-hinokiresinol (t-HL) exhibited significant inhibitory effects on the NO production in a dose-dependent manner with IC50 values of 11.91 and 39.08 μM, respectively. Immunoblotting demonstrated that TBIII and t-HL suppressed NO production by inhibiting the expressions of iNOS in LPS-stimulated N9 microglial cells. Further results revealed that pretreatment of N9 microglial cells with TBIII and t-HL attenuated the LPS-induced expression tumor necrosis factor (TNF)-α and interleukin-6 (IL-6) at mRNAs and protein levels. Moreover, the activation of nuclear factor-κB (NF-κB) and phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathways were inhibited by TBIII and t-HL, respectively. Our findings indicate that the therapeutic implication of TBIII and t-HL for neurogenerative disease associated with neuroinflammation.

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α-Lipoic acid suppresses osteoclastogenesis despite increasing the receptor activator of nuclear factor κB ligand/osteoprotegerin ratio in human bone marrow stromal cells

Journal of Endocrinology ◽

10.1677/joe.1.05995 ◽

2005 ◽

Vol 185 (3) ◽

pp. 401-413 ◽

Cited By ~ 18

Author(s):

Jung-Min Koh ◽

Young-Sun Lee ◽

Chang-Hyun Byun ◽

Eun-Ju Chang ◽

Hyunsoo Kim ◽

...

Keyword(s):

Bone Marrow ◽

Lipoic Acid ◽

Nuclear Factor Κb ◽

Human Bone ◽

Human Bone Marrow ◽

Mouse Bone Marrow ◽

Dependent Manner ◽

Nuclear Factor ◽

Receptor Activator ◽

Dose Dependent

Growing evidence has shown a biochemical link between increased oxidative stress and reduced bone density. Although α-lipoic acid (α-LA) has been shown to act as a thiol antioxidant, its effect on bone cells has not been determined. Using proteomic analysis, we identified six differentially expressed proteins in the conditioned media of α-LA-treated human bone marrow stromal cell line (HS-5). One of these proteins, receptor activator of nuclear factor κB ligand (RANKL), was significantly up-regulated, as confirmed by immunoblotting with anti-RANKL antibody. ELISA showed that α-LA stimulated RANKL production in cellular extracts (membranous RANKL) about 5-fold and in conditioned medium (soluble RANKL) about 23-fold, but had no effect on osteoprotegerin (OPG) secretion. Despite increasing the RANKL/OPG ratio, α-LA showed a dose-dependent suppression of osteoclastogenesis, both in a coculture system of mouse bone marrow cells and osteoblasts and in a mouse bone marrow cell culture system, and reduced bone resorption in a dose-dependent manner. In addition, α-LA-induced soluble RANKL was not inhibited by matrix metalloprotease inhibitors, indicating that soluble RANKL is produced by α-LA without any posttranslational processing. In contrast, α-LA had no significant effect on the proliferation and differentiation of HS-5 cells. These results suggest that α-LA suppresses osteoclastogenesis by directly inhibiting RANKL–RANK mediated signals, not by mediating cellular RANKL production. In addition, our findings indicate that α-LA-induced soluble RANKL is not produced by shedding of membranous RANKL.

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Macrophage inflammatory protein-1α is an osteoclastogenic factor in myeloma that is independent of receptor activator of nuclear factor κB ligand

Blood ◽

10.1182/blood.v97.11.3349 ◽

2001 ◽

Vol 97 (11) ◽

pp. 3349-3353 ◽

Cited By ~ 244

Author(s):

Je-Ho Han ◽

Sun Jin Choi ◽

Noriyoshi Kurihara ◽

Masanori Koide ◽

Yasuo Oba ◽

...

Keyword(s):

Stromal Cells ◽

Nuclear Factor Κb ◽

Marrow Stromal Cells ◽

Dependent Manner ◽

Nuclear Factor ◽

Myeloma Cells ◽

Parathyroid Hormone Related Protein ◽

Inflammatory Protein ◽

Receptor Activator ◽

Macrophage Inflammatory Protein

A complementary DNA expression library derived from marrow samples from myeloma patients was recently screened and human macrophage inflammatory protein-1α (hMIP-1α) was identified as an osteoclastogenic factor expressed in these samples. hMIP-1α enhanced osteoclast (OCL) formation in human marrow cultures and by highly purified OCL precursors in a dose-dependent manner (5-200 pg/mL). Furthermore, hMIP-1α enhanced OCL formation induced by human interleukin-6 (IL-6), which is produced by marrow stromal cells when they interact with myeloma cells. hMIP-1α also enhanced OCL formation induced by parathyroid hormone-related protein (PTHrP) and receptor activator of nuclear factor κB ligand (RANKL), factors also implicated in myeloma bone disease. Time-course studies revealed that the hMIP-1α acted during the last 2 weeks of the 3-week culture period. Reverse transcription–polymerase chain reaction analysis showed that the chemokine receptors for hMIP-1α (CCR1 and CCR5) were expressed by human bone marrow and highly purified early OCL precursors. Furthermore, hMIP-1α did not increase expression of RANKL. These data demonstrate that hMIP-1α is an osteoclastogenic factor that appears to act directly on human OCL progenitors and acts at the later stages of OCL differentiation. These data further suggest that in patients with myeloma, MIP-1α produced by myeloma cells, in combination with RANKL and IL-6 that are produced by marrow stromal cells in response to myeloma cells, enhances OCL formation through their combined effects on OCL precursors.

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PGRN Induces Impaired Insulin Sensitivity and Defective Autophagy in Hepatic Insulin Resistance

Molecular Endocrinology ◽

10.1210/me.2014-1266 ◽

2015 ◽

Vol 29 (4) ◽

pp. 528-541 ◽

Cited By ~ 21

Author(s):

Jiali Liu ◽

Huixia Li ◽

Bo Zhou ◽

Lin Xu ◽

Xiaomin Kang ◽

...

Keyword(s):

Insulin Resistance ◽

Insulin Sensitivity ◽

Insulin Signaling ◽

Nuclear Factor Κb ◽

Hepatic Insulin Resistance ◽

Causative Role ◽

Dependent Manner ◽

Nuclear Factor ◽

Impaired Insulin

Abstract Progranulin (PGRN) has recently emerged as an important regulator for glucose metabolism and insulin sensitivity. However, the underlying mechanisms of PGRN in the regulation of insulin sensitivity and autophagy remain elusive. In this study, we aimed to address the direct effects of PGRN in vivo and to evaluate the potential interaction of impaired insulin sensitivity and autophagic disorders in hepatic insulin resistance. We found that mice treated with PGRN for 21 days exhibited the impaired glucose tolerance and insulin tolerance and hepatic autophagy imbalance as well as defective insulin signaling. Furthermore, treatment of mice with TNF receptor (TNFR)-1 blocking peptide-Fc, a TNFR1 blocking peptide-Fc fusion protein to competitively block the interaction of PGRN and TNFR1, resulted in the restoration of systemic insulin sensitivity and the recovery of autophagy and insulin signaling in liver. Consistent with these findings in vivo, we also observed that PGRN treatment induced defective autophagy and impaired insulin signaling in hepatocytes, with such effects being drastically nullified by the addition of TNFR1 blocking peptide -Fc or TNFR1-small interference RNA via the TNFR1-nuclear factor-κB-dependent manner, indicating the causative role of PGRN in hepatic insulin resistance. In conclusion, our findings supported the notion that PGRN is a key regulator of hepatic insulin resistance and that PGRN may mediate its effects, at least in part, by inducing defective autophagy via TNFR1/nuclear factor-κB.

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Extracellular ASC exacerbated the recurrent ischemic stroke in an NLRP3-dependent manner

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x19856226 ◽

2019 ◽

Vol 40 (5) ◽

pp. 1048-1060 ◽

Cited By ~ 8

Author(s):

Xiao-fei He ◽

Yi-xuan Zeng ◽

Ge Li ◽

Yu-kun Feng ◽

Cheng Wu ◽

...

Keyword(s):

Ischemic Stroke ◽

Mouse Model ◽

Inflammatory Responses ◽

Recurrent Stroke ◽

Nuclear Factor Κb ◽

Mrna Levels ◽

Dependent Manner ◽

Wild Type ◽

Infarct Area ◽

Recurrent Strokes

Using a photothrombotic mouse model of single stroke, we show that a single stroke onset increases the nuclear factor-κB (NF-κB), NLR family CARD domain containing protein 4 (NLRC4), and absent in melanoma 2 (AIM2) inflammasomes, as well as the mRNA levels of NLRP3. Next, using a photothrombotic mouse model of recurrent stroke, we found that recurrent strokes increased the activation of NLRP3, exacerbated the brain damage and the pro-inflammatory response in wild type (WT) mice, but not in NLRP3 knockout ( NLRP3 KO) mice. Additionally, we found that apoptosis-associated speck-like protein containing a CARD (ASC) protein level surrounding the infarct area was comparatively increased, but that ASC specks outside of microglia in both the ipsilateral and contralateral of stroke site were decreased in NLRP3 KO mice relative to wild-type (WT) controls, and the number of ASC specks surrounding the second infarct area was positively correlated to the damage scores. Mechanistically, we found that recombinant ASC (RecASC) activated NLRP3 and induced pro-inflammatory responses, exacerbating the outcome of ischemic stroke, in WT mice, but not in NLRP3 KO mice. We therefore conclude that the NLRP3 inflammasome is activated by two attacks of stroke, which act together with ASC to exacerbate recurrent strokes.

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