Trif is not required for immune complex glomerulonephritis: dying cells activate mesangial cells via Tlr2/Myd88 rather than Tlr3/Trif

2009 ◽  
Vol 296 (4) ◽  
pp. F867-F874 ◽  
Author(s):  
Julia Lichtnekert ◽  
Volker Vielhauer ◽  
Daniel Zecher ◽  
Onkar P. Kulkarni ◽  
Sebastian Clauss ◽  
...  
Keyword(s):  
Mesangial Cells ◽  
Apoptotic Cell ◽  
Dependent Manner ◽  
Glomerular Mesangial Cells ◽  
Wild Type ◽  
Tlr Agonists ◽  
Rabbit Igg ◽  
Dying Cells ◽  
Myd88 Signaling ◽  
Deficient Mice

Viral RNA or bacterial products can activate glomerular mesangial cells via a subset of Toll-like receptors (Tlr). Because Tlr2-deficient mice were recently found to have attenuated nephrotoxic serum nephritis (NSN), we hypothesized that endogenous Tlr agonists can activate glomerular mesangial cells. Primary mesangial cells from C57BL/6 mice expressed Tlr1-6 and Tlr11 mRNA at considerable levels and produced Il-6 when being exposed to the respective Tlr ligands. Exposure to necrotic cells activated cultured primary mesangial cells to produce Il-6 in a Tlr2/Myd88-dependent manner. Apoptotic cells activated cultured mesangial cells only when being enriched to high numbers. Apoptotic cell-induced Il-6 release was Myd88 dependent, and only purified apoptotic cell RNA induced Trif signaling in mesangial cells. Does Trif signaling contribute to disease activity in glomerulonephritis? To answer this question, we induced autologous NSN by injection of NS raised in rabbits in Trif-mutant and wild-type mice. Lack of Trif did not alter the functional and histomorphological abnormalities of NSN, including the evolution of anti-rabbit IgG and anti-rabbit-specific nephritogenic T cells. We therefore conclude that apoptotic cell RNA is a poor activator of Trif signaling in mesangial cells and that necrotic cells' releases rather activate mesangial cells via the Tlr2/Myd88 signaling pathway.

Platelet-activating factor and the kidney

1986 ◽  
Vol 251 (1) ◽  
pp. F1-F11 ◽  
Author(s):  
D. Schlondorff ◽  
R. Neuwirth
Keyword(s):  
De Novo ◽  
Mesangial Cells ◽  
Biological Activities ◽  
Platelet Activating Factor ◽  
Calcium Ionophore ◽  
Initial Step ◽  
Renal Physiology ◽  
Dependent Manner ◽  
Glomerular Mesangial Cells ◽  
Isolated Kidney

Platelet-activating factor (PAF) represents a group of phospholipids with the basic structure of 1-alkyl-2-acetyl-sn-glycero-3-phosphocholine. A number of different cells are capable of producing PAF in response to various stimuli. The initial step of PAF formation is activation of phospholipase A2 in a calcium-dependent manner, yielding lyso-PAF. During this step arachidonic acid is also released and can be converted to its respective cyclooxygenase and lipoxygenase products. The lyso-PAF generated is then acetylated in position 2 of the glycerol backbone by a coenzyme A (CoA)-dependent acetyltransferase. An additional pathway may exist whereby PAF is generated de novo from 1-alkyl-2-acetyl-sn-glycerol by phosphocholine transferase. PAF inactivation in cells and blood is by specific acetylhydrolases. PAF exhibits a variety of biological activities including platelet and leukocyte aggregation and activation, increased vascular permeability, respiratory distress, decreased cardiac output, and hypotension. In the kidney PAF can produce decreases in blood flow, glomerular filtration, and fluid and electrolyte excretion. Intrarenal artery injection of PAF may also result in glomerular accumulation of platelets and leukocytes and mild proteinuria. PAF increases prostaglandin formation in the isolated kidney and in cultured glomerular mesangial cells. PAF also causes contraction of mesangial cells. Upon stimulation with calcium ionophore the isolated kidney, isolated glomeruli and medullary cells, and cultured mesangial cells are capable of producing PAF. The potential role for PAF in renal physiology and pathophysiology requires further investigation that may be complicated by 1) the multiple interactions of PAF, prostaglandins, and leukotrienes and 2) the autocoid nature of PAF, which may restrict its action to its site of generation.

scholarly journals Tumor necrosis factor alpha activates soluble guanylate cyclase in bovine glomerular mesangial cells via an L-arginine-dependent mechanism.

1990 ◽  
Vol 172 (6) ◽  
pp. 1843-1852 ◽  
Author(s):  
P A Marsden ◽  
B J Ballermann
Keyword(s):  
Guanylate Cyclase ◽  
Mesangial Cell ◽  
Soluble Guanylate Cyclase ◽  
Mesangial Cells ◽  
Tnf Alpha ◽  
Dependent Manner ◽  
Glomerular Mesangial Cells ◽  
Concentration Dependent Manner ◽  
Necrosis Factor Alpha ◽  
Factor Alpha

Endothelium-derived nitric oxide (NO) causes vasodilatation by activating soluble guanylate cyclase, and glomerular mesangial cells respond to NO with elevations of intracellular guanosine 3',5'-cyclic monophosphate (cGMP). We explored whether mesangial cells can be stimulated to produce NO and whether NO modulates mesangial cell function in an autocrine or paracrine fashion. Tumor necrosis factor alpha (TNF-alpha) raised mesangial cell cGMP levels in a time- and concentration-dependent manner (threshold dose 1 ng/ml, IC50 13.8 ng/ml, maximal response 100 ng/ml). TNF-alpha-induced increases in mesangial cGMP content were evident at 8 h and maximal at 18-24 h. The TNF-alpha-induced stimulation of mesangial cell cGMP production was abrogated by actinomycin D or cycloheximide suggesting dependence on new RNA or protein synthesis. Hemoglobin and methylene blue, both known to inhibit NO action, dramatically reduced TNF-alpha-induced mesangial cell cGMP production. Superoxide dismutase, known to potentiate NO action, augmented the TNF-alpha-induced effect. Ng-monomethyl-L-arginine (L-NMMA) decreased cGMP levels in TNF-alpha-treated, but not vehicle-treated mesangial cells in a concentration-dependent manner (IC50 53 microM). L-arginine had no effect on cGMP levels in control or TNF-alpha-treated mesangial cells but reversed L-NMMA-induced inhibition. Interleukin 1 beta and lipopolysaccharide (LPS), but not interferon gamma, also increased mesangial cell cGMP content. Transforming growth factor beta 1 blunted the mesangial cell response to TNF-alpha. TNF-alpha-induced L-arginine-dependent increases in cGMP were also evident in bovine renal artery vascular smooth muscle cells, COS-1 cells, and 1502 human fibroblasts. These findings suggest that TNF-alpha induces expression in mesangial cell of an enzyme(s) involved in the formation of L-arginine-derived NO. Moreover, the data indicate that NO acts in an autocrine and paracrine fashion to activate mesangial cell soluble guanylate cyclase. Cytokine-induced formation of NO in mesangial and vascular smooth muscle cells may be implicated in the pathogenesis of septic shock.

scholarly journals High Glucose and Lipopolysaccharide Prime NLRP3 Inflammasome via ROS/TXNIP Pathway in Mesangial Cells

2016 ◽  
Vol 2016 ◽  
pp. 1-11 ◽  
Author(s):  
Hong Feng ◽  
Junling Gu ◽  
Fang Gou ◽  
Wei Huang ◽  
Chenlin Gao ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Nlrp3 Inflammasome ◽  
High Glucose ◽  
Mesangial Cells ◽  
Central Component ◽  
Dependent Manner ◽  
Glomerular Mesangial Cells ◽  
Interacting Protein

While inflammation is considered a central component in the development in diabetic nephropathy, the mechanism remains unclear. The NLRP3 inflammasome acts as both a sensor and a regulator of the inflammatory response. The NLRP3 inflammasome responds to exogenous and endogenous danger signals, resulting in cleavage of procaspase-1 and activation of cytokines IL-1β, IL-18, and IL-33, ultimately triggering an inflammatory cascade reaction. This study observed the expression of NLRP3 inflammasome signaling stimulated by high glucose, lipopolysaccharide, and reactive oxygen species (ROS) inhibitor N-acetyl-L-cysteine in glomerular mesangial cells, aiming to elucidate the mechanism by which the NLRP3 inflammasome signaling pathway may contribute to diabetic nephropathy. We found that the expression of thioredoxin-interacting protein (TXNIP), NLRP3, and IL-1βwas observed by immunohistochemistry in vivo. Simultaneously, the mRNA and protein levels of TXNIP, NLRP3, procaspase-1, and IL-1βwere significantly induced by high glucose concentration and lipopolysaccharide in a dose-dependent and time-dependent manner in vitro. This induction by both high glucose and lipopolysaccharide was significantly inhibited by N-acetyl-L-cysteine. Our results firstly reveal that high glucose and lipopolysaccharide activate ROS/TXNIP/ NLRP3/IL-1βinflammasome signaling in glomerular mesangial cells, suggesting a mechanism by which inflammation may contribute to the development of diabetic nephropathy.

Abstract 80: Accumulation of Mitochondrial DNA in Autolysosome Causes Inflammation and Heart Failure Through Toll-Like Receptor 9 (TLR9) Signaling

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Takafumi Oka ◽  
Osamu Yamaguchi ◽  
Issei Komuro ◽  
Kinya Otsu
Keyword(s):  
Heart Failure ◽  
Mitochondrial Dna ◽  
Nuclear Dna ◽  
Apoptotic Cell ◽  
Pressure Overload ◽  
Wild Type ◽  
Dnase Ii ◽  
Cardiac Phenotype ◽  
Deficient Mice ◽  
Tlr9 Signaling

Backgrounds Nuclear DNA in apoptotic cell is digested by lysosomal deoxyribonuclease II (DNase II) in macrophages. Improper DNA digestion can lead to inflammation. We previously reported that cardiac-specific DNase II-deficient mice (CKO) exhibited heart failure after transverse aortic constriction (TAC). We observed inflammatory response and DNA accumulation in autolysosome in TAC-operated CKO heart. They were considered to be mitochondrial DNA (mtDNA). In present study, we elucidated the mechanism of inflammation integrated by DNA accumulation in TAC-operated CKO hearts. Furthermore we investigated the pathogenesis of inflammation and heart failure in wild-typeTAC-operated mice. Methods & Results First, we identified the origin of accumulated DNA in lysosome. To label cardiac mtDNA, EdU (5-ethynyl 2’ deoxyuridine) were injected into mice before TAC. In TAC-operated CKO mice, EdU- and LAMP2a (lysosomal marker) or LC3 (autophagosome marker) positive deposits were observed, indicating that mtDNA accumulated in autolysosome. Then, we examined the mechanism how the mtDNA accumulation leads to inflammation. mtDNA has similarities to bacterial DNA, which contains inflammatogenic unmethylated CpG motif. TLR9, localized in the endolysosome, senses DNA with unmethylated CpG motifs. Therefore, we hypothesized that undigested mtDNA is sensed by TLR9. We administrated the inhibitory oligodeoxynucleotides against TLR9 to TAC-operated CKO mice. They attenuated the development of cardiomyopathy in CKO mice. Ablation of Tlr9 also canceled the cardiac phenotype of CKO mice. Next, we examined the involvement of DNA accumulation and TLR9 signaling in wild-type TAC-operated mice. DNase II activity was up-regulated in hypertrophied hearts, but not in failing hearts. LAMP2a- or LC3- positive DNA accumulation was observed in failing hearts. To determine the significance of TLR9 signaling pathway in the pathogenesis of heart failure, we subjected TLR9-deficient mice to TAC. They showed significant resistance to pressure-overload. TLR9-inhibitory oligodeoxynucleotides also improved the mortality in wild-type TAC-operated mice. Conclusion mtDNA-TLR9 axis is involved in inflammation in failing hearts in response to pressure overload.

scholarly journals RIPK2-Mediated Autophagy and Negatively Regulated ROS-NLRP3 Inflammasome Signaling in GMCs Stimulated with High Glucose

2019 ◽  
Vol 2019 ◽  
pp. 1-13 ◽  
Author(s):  
Chenlin Gao ◽  
Jiao Chen ◽  
Fang Fan ◽  
Yang Long ◽  
Shi Tang ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
High Glucose ◽  
Mesangial Cells ◽  
Vital Role ◽  
Dependent Manner ◽  
Glomerular Mesangial Cells ◽  
Interacting Protein ◽  
High Glucose Group ◽  
Glucose Group

Background. Hyperglycemia plays a vital role in diabetic nephropathy (DN); autophagy and its potential upregulator receptor-interacting protein kinase 2 (RIPK2) are associated with ROS, which play a potential role in regulating NLRP3, and may be involved in inflammation in DN. Aim. In this study, we aimed to explore the mechanisms mediated by RIPK2 in autophagy and the relationship with ROS-NLRP3 of DN, by investigating the levels of RIPK2 and autophagy in glomerular mesangial cells (GMCs) stimulated with high glucose. Material and Methods. GMCs were divided into the following groups: normal group (NC), high glucose group (HG), and RIPK2 siRNA group. RIPK2, LC3, caspase1, and IL-1β levels were measured by western blotting and RT-PCR. Autophagosomes were measured by GFP-RFP-LC3; ROS were detected by DCFH-DA. Results. High glucose upregulated RIPK2 and LC3 in GMCs during short periods (0-12 h) (p<0.01), while RIPK2 and LC3 were significantly downregulated in the long term (12-72 h) (p<0.01); these changes were positively correlated with glucose concentration (p<0.01). In addition, levels of ROS, caspase1, and IL-1β increased in a time- and dose-dependent manner in the high glucose group, even with an increased expression of LC3 (p<0.01). However, LC3 expression decreased in the siRIPK2 group, while levels of ROS, caspase1, and IL-1β increased (p<0.01). Conclusions. Autophagy was activated by high glucose at short time periods but was inhibited in the long term, demonstrating a dual role for high glucose in autophagy of GMCs. RIPK2 regulates ROS-NLRP3 inflammasome signaling through autophagy and may be involved in the pathogenesis of DN.

Regulation of mesangial cell cyclooxygenase synthesis by cytokines and glucocorticoids

1992 ◽  
Vol 263 (1) ◽  
pp. F97-F102 ◽  
Author(s):  
D. W. Coyne ◽  
M. Nickols ◽  
W. Bertrand ◽  
A. R. Morrison
Keyword(s):  
Time Course ◽  
Mesangial Cell ◽  
Mesangial Cells ◽  
Interleukin 1 ◽  
Cell Types ◽  
Dependent Manner ◽  
Glomerular Mesangial Cells ◽  
Prostaglandin Production ◽  
Arachidonate Release ◽  
Necrosis Factor

The cytokines, interleukin-1 (IL-1) and tumor necrosis factor (TNF), potently induce prostaglandin formation in glomerular mesangial cells. Mechanisms by which these cytokines stimulate prostaglandin formation vary among cell types. We investigated whether alterations in phospholipase A2 (PLA2) or cyclooxygenase (COX) mass and activity contribute to the changes in mesangial cell prostaglandin production. These cytokines induced COX activity and mass in a time-dependent manner, which paralleled prostaglandin production. IL-1 increased COX mass approximately threefold by 24 h. TNF had a much smaller effect, although it appeared to be additive with IL-1. IL-1-induced COX mass was maintained at an increased level for at least 48 h. The glucocorticoid dexamethasone (DEX) virtually abolished prostaglandin production and blocked cytokine induction of COX activity and mass. DEX did not reduce COX activity or mass below the basal, serum-fed levels, however. By utilizing stable isotope methods, we could demonstrate that IL-1 increased free arachidonate levels, implying new PLA2 synthesis over a time course that was maximal at 6 h and was cycloheximide and actinomycin D sensitive. These data demonstrate that the cytokines IL-1 and TNF enhance synthesis of COX and PLA2, contributing to increased prostaglandin production. Cytokine-stimulated prostaglandin production ceases when cells are also treated with DEX, although control levels of COX activity and mass remain. This occurs because DEX inhibits the IL-1-induced enhanced arachidonate release.

Immune complex activation of rat glomerular mesangial cells: dependence on the Fc region of antibody

1989 ◽  
Vol 257 (3) ◽  
pp. F478-F485
Author(s):  
T. C. Knauss ◽  
P. Mene ◽  
S. A. Ricanati ◽  
M. Kester ◽  
G. R. Dubyak ◽  
...  
Keyword(s):  
Specific Antibody ◽  
Mesangial Cell ◽  
Mesangial Cells ◽  
Inositol Phosphates ◽  
Exchange Chromatography ◽  
Water Soluble ◽  
Free Calcium ◽  
Dependent Manner ◽  
Glomerular Mesangial Cells ◽  
Cross Sectional

Glomerulonephritis is frequently associated with immunoglobulin deposition in the mesangium. We had previously shown that contractile, rat mesangial cells in culture synthesize superoxide anion after binding immune complexes (IC) in a manner dependent on the Fc region of immunoglobulin G (IgG). We now studied the effects of soluble IC on mesangial cell cytosolic free calcium ([Ca2+]i) and phosphatidylinositol turnover as putative mechanisms of transmembrane signaling as well as prostaglandin biosynthesis and contraction. IC (500 micrograms specific antibody) raised [Ca2+]i in mesangial cells loaded with fura-2 from resting levels of 100.4 +/- 8.0 to a peak of 282.3 +/- 31.5 nM in a dose-dependent manner. Removal of extracellular Ca2+ by ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid only slightly reduced peak, IC-stimulated [Ca2+]i to 236 +/- 18 nM but prevented the sustained phase of the response, indicating that IC both mobilized Ca2+ from intracellular stores and increased the influx of Ca2+ across the plasma membrane. IC did not increase water-soluble inositol phosphates, measured by anion-exchange chromatography of trichloroacetic acid-extracted cells but markedly stimulated PGE2 and thromboxane B2 synthesis in a dose- and time-dependent manner. Finally, IC (250 micrograms specific antibody) induced 45.8 +/- 10.1% of the cells to contract with an average decrease in cross-sectional surface area of 20.0 +/- 1.8% of basal as assessed by image-analysis microscopy. IC formed with F(ab')2 fragments of antibody and antigen or mixtures of antigen and nonimmune whole molecule antibody did not alter [Ca2+]i, induce prostaglandin synthesis, or stimulate mesangial cell contraction.(ABSTRACT TRUNCATED AT 250 WORDS)

Lactadherin and Clearance of Platelet-Derived Microvesicles.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1840-1840
Author(s):  
Swapan Kumar Dasgupta ◽  
Hanan Abdel-Monem ◽  
Polly Niravath ◽  
Anhquyen Le ◽  
Ricardo Bellera ◽  
...  
Keyword(s):  
Milk Fat ◽  
Mammalian Cells ◽  
Procoagulant Activity ◽  
In Vivo Model ◽  
Maximal Effect ◽  
Dependent Manner ◽  
Wild Type ◽  
Membrane Bilayer ◽  
Anionic Phospholipids ◽  
Deficient Mice

Abstract Objective— In platelets, as in most mammalian cells, the anionic phospholipids such as phosphatidylserine are present only in the inner leaflet of the membrane bilayer. During platelet activation, phosphatidylserine moves from the inner to the outer leaflet of the membrane bilayer. The transbilayer movement of phosphatidylserine is responsible for platelet procoagulant activity as the exposed phosphatidylserine provides high affinity binding sites for the assembly of the prothrombinase and tenase complex. Externalization of anionic phospholipids in platelet is accompanied by the release of phosphatidylserine-rich microvesicles. These microvesicles account for the procoagulant activity of plasma by providing an efficient catalytic surface. Lactadherin, also known milk fat globule-EGF 8, is a 45 kDa glycoprotein secreted by macrophages. Lactadherin contains EGF-like domains at the amino terminus and two C-domains at the carboxy terminus that share homology to the phosphatidylserinebinding domains of blood coagulation factors V and VIII. Lactadherin binds to apoptotic lymphocytes and phosphatidylserine-expressing red blood cells via the C-domains and anchors them to macrophage integrins via its RGD sequence in the EGF domain. We have examined the role of lactadherin in clearance of phosphatidylserine-rich platelet-derived microvesicles. Methods and Results—Platelet-derived microvesicles were labeled with the fluorophore BODIPY-maleimide and incubated with THP-1 cell derived macrophages. The extent of phagocytosis was quantified by measuring the intracellular fluorescence by flow cytometry. Lactadherin promoted phagocytosis in a concentration-dependent manner with a half-maximal effect at ~ 5 ng/ml. A monoclonal antibody to lactadherin and a carboxy terminal fragment of lactadherin inhibited lactadherin-dependent phagocytosis. Lactadherin-deficient mice had increased number of microvesicles in their plasma and generated more thrombin compared to their wild type littermates. In addition, splenic macrophages from lactadherin-deficient mice showed decreased capacity to phagocytose platelet microvesicles. Finally, in a in vivo model of light/dye-induced endothelial injury/ thrombosis model, lactadherin-deficient mice, showed enhanced thrombus formation (5.93 ± 0.43 min) compared to their wild-type littermates ( 9.80 ± 1.14 min; P=0.01, n=9 in each group) in the cremastric venules. Conclusion— Our studies show that lactadherin mediates the clearance of PS expressing platelet-derived microvesicles from the circulation and that a defective clearance can induce a hypercoagulable state.

scholarly journals Abundance of TRPC6 protein in glomerular mesangial cells is decreased by ROS and PKC in diabetes

2011 ◽  
Vol 301 (2) ◽  
pp. C304-C315 ◽  
Author(s):  
Sarabeth Graham ◽  
Yves Gorin ◽  
Hanna E. Abboud ◽  
Min Ding ◽  
Duck Yoon Lee ◽  
...  
Keyword(s):  
Nadph Oxidase ◽  
Protein Expression ◽  
Transient Receptor Potential ◽  
Cultured Cells ◽  
Mesangial Cells ◽  
Receptor Potential ◽  
Underlying Mechanism ◽  
Diabetic Rats ◽  
Dependent Manner ◽  
Glomerular Mesangial Cells

The present study was performed to investigate the underlying mechanism, particularly the roles of reactive oxygen species (ROS) and protein kinase C (PKC), in the diabetes-induced canonical transient receptor potential 6 (TRPC6) downregulation. We found that high glucose (HG) significantly reduced TRPC6 protein expression in cultured mesangial cells (MCs). TRPC6 protein was also significantly reduced in the glomeruli but not in the heart or aorta isolated from streptozotocin-induced diabetic rats. In the cultured MCs, H2O2 suppressed TRPC6 protein expression in a dose- and time-dependent manner, which emulated the HG effect. Catalase as well as superoxide dismutase were able to prevent the inhibitory effect of HG on TRPC6. The antioxidant effect observed in cultured cells was also observed in diabetic rats treated with tempol for 2 wk, which exhibited a preservation of TRPC6 in the glomeruli. Specific knockdown of Nox4, a component of NADPH oxidase, increased TRPC6 protein expression. Furthermore, the PKC activator phorbol 12-myristate 13-acetate (PMA), but not its analog 4α-phorbol 12, 13-didecanoate (4α-PDD), suppressed TRPC6 expression, and this PMA effect was not affected by catalase. Moreover, Gö6976, but not LY333531, attenuated the negative effect of HG on TRPC6 expression. Gö6976 also inhibited H2O2 effect on TRPC6. Furthermore, either knockdown of TRPC6 or HG treatment significantly decreased ANG II-stimulated MC contraction, and the HG-impaired MC contraction was rescued by overexpression of TRPC6. These results suggest that hyperglycemia in diabetes downregulated TRPC6 protein expression in MCs through a NADPH oxidase Nox4-ROS-PKC pathway, proving a mechanism for impaired MC contraction in diabetes.

scholarly journals Differential Role of MyD88 in Macrophage-Mediated Responses to Opportunistic Fungal Pathogens

2003 ◽  
Vol 71 (9) ◽  
pp. 5280-5286 ◽  
Author(s):  
Kieren A. Marr ◽  
S. Arunmozhi Balajee ◽  
Thomas R. Hawn ◽  
Adrian Ozinsky ◽  
Uyenvy Pham ◽  
...  
Keyword(s):  
Fungal Pathogens ◽  
Cytokine Production ◽  
Pathogenic Fungi ◽  
Adapter Protein ◽  
Wild Type ◽  
Intracellular Killing ◽  
Pathogenic Yeast ◽  
Myd88 Signaling ◽  
Deficient Mice

ABSTRACT Toll-like receptors mediate macrophage recognition of microbial ligands, inducing expression of microbicidal molecules and cytokines via the adapter protein MyD88. We investigated the role of MyD88 in regulating murine macrophage responses to a pathogenic yeast (Candida albicans) and mold (Aspergillus fumigatus). Macrophages derived from bone marrow of MyD88-deficient mice (MyD88−/−) demonstrated impaired phagocytosis and intracellular killing of C. albicans compared to wild-type (MyD88+/+) macrophages. In contrast, ingestion and killing of A. fumigatus conidia was MyD88 independent. Cytokine production by MyD88−/− macrophages in response to C. albicans yeasts and hyphae was substantially decreased, but responses to A. fumigatus hyphae were preserved. These results provide evidence that MyD88 signaling is involved in phagocytosis and killing of live C. albicans, but not A. fumigatus. The differential role of MyD88 may represent one mechanism by which macrophages regulate innate responses specific to different pathogenic fungi.

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