Mycobacterium tuberculosis stimulates IL-1β production by macrophages in an ESAT-6 dependent manner with the involvement of serum amyloid A3

ABSTRACTTo explore interleukin (IL)-1β production in tuberculosis, we infected mouse bone marrow-derived macrophages (BMDM) with Mycobacterium tuberculosis (Mtb) H37Rv, its early secreted antigenic target protein of 6 kDa (ESAT-6) gene deletion (H37Rv:Δ3875) or complemented strain (H37Rv:Δ3875C) and evaluated IL-1β production. H37Rv induced significantly increased IL-1β production by BMDMs compared to non-infected BMDMs. In contrast, H37Rv:Δ3875 induced significantly less mature IL-1β production despite eliciting comparable levels of pro-IL-1β and IL-8 from BMDMs compared to H37Rv and H37Rv:Δ3875C. Blocking either NLRP3 or K+ efflux diminished H37Rv-induced IL-1β production by BMDMs. Infection of mice intranasally with H37Rv:Δ3875 induced less IL-1β production in the lungs compared with H37Rv.Intranasal delivery of ESAT-6 but not CFP10 induced production of IL-1β in mouse lungs and RNA-Seq analysis identified serum amyloid A (SAA) 3 as one of the highly expressed genes in mouse lungs. Infection of mice with H37Rv but not H37Rv:Δ3875 induced expression of lung SAA3 mRNA and protein, consistent with the effect of intranasal delivery of ESAT-6. Silencing SAA3 reduced Mtb-induced IL-1β production by BMDMs. We conclude that the production of SAA3 is required for Mtb stimulated IL-1β production by macrophages in tuberculosis infection.

Download Full-text

Mycobacterium tuberculosis Binds Human Serum Amyloid A and the Interaction Modulates the Colonization of Human Macrophages and the Transcriptional Response of the Pathogen

Cells ◽

10.3390/cells10051264 ◽

2021 ◽

Vol 10 (5) ◽

pp. 1264

Author(s):

Malwina Kawka ◽

Anna Brzostek ◽

Katarzyna Dzitko ◽

Jakub Kryczka ◽

Radosław Bednarek ◽

...

Keyword(s):

Mycobacterium Tuberculosis ◽

Serum Amyloid A ◽

Acute Phase Protein ◽

Transcriptional Response ◽

Serum Amyloid ◽

Host Protein ◽

Binding Interaction ◽

Human Macrophages ◽

Amyloid A ◽

Transporter Systems

As a very successful pathogen with outstanding adaptive properties, Mycobacterium tuberculosis (Mtb) has developed a plethora of sophisticated mechanisms to subvert host defenses and effectively enter and replicate in the harmful environment inside professional phagocytes, namely, macrophages. Here, we demonstrated the binding interaction of Mtb with a major human acute phase protein, namely, serum amyloid A (SAA1), and identified AtpA (Rv1308), ABC (Rv2477c), EspB (Rv3881c), TB 18.6 (Rv2140c), and ThiC (Rv0423c) membrane proteins as mycobacterial effectors responsible for the pathogen-host protein interplay. SAA1-opsonization of Mtb prior to the infection of human macrophages favored bacterial entry into target phagocytes accompanied by a substantial increase in the load of intracellularly multiplying and surviving bacteria. Furthermore, binding of human SAA1 by Mtb resulted in the up- or downregulation of the transcriptional response of tubercle bacilli. The most substantial changes were related to the increased expression level of the genes of two operons encoding mycobacterial transporter systems, namely, mmpL5/mmpS5 (rv0676c), and rv1217c, rv1218c. Therefore, we postulate that during infection, Mtb-SAA1 binding promotes the infection of host macrophages by tubercle bacilli and modulates the functional response of the pathogen.

Download Full-text

Serum amyloid A induces endothelial dysfunction in porcine coronary arteries and human coronary artery endothelial cells

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00238.2008 ◽

2008 ◽

Vol 295 (6) ◽

pp. H2399-H2408 ◽

Cited By ~ 34

Author(s):

Xinwen Wang ◽

Hong Chai ◽

Zehao Wang ◽

Peter H. Lin ◽

Qizhi Yao ◽

...

Keyword(s):

Endothelial Cells ◽

Coronary Artery ◽

Endothelial Dysfunction ◽

Coronary Arteries ◽

Molecular Mechanisms ◽

Serum Amyloid A ◽

Serum Amyloid ◽

Dependent Manner ◽

Amyloid A ◽

Enos Mrna

The objective of this study was to determine the effects and mechanisms of serum amyloid A (SAA) on coronary endothelial function. Porcine coronary arteries and human coronary arterial endothelial cells (HCAECs) were treated with SAA (0, 1, 10, or 25 μg/ml). Vasomotor reactivity was studied using a myograph tension system. SAA significantly reduced endothelium-dependent vasorelaxation of porcine coronary arteries in response to bradykinin in a concentration-dependent manner. SAA significantly decreased endothelial nitric oxide (NO) synthase (eNOS) mRNA and protein levels as well as NO bioavailability, whereas it increased ROS in both artery rings and HCAECs. In addition, the activities of internal antioxidant enzymes catalase and SOD were decreased in SAA-treated HCAECs. Bio-plex immunoassay analysis showed the activation of JNK, ERK2, and IκB-α after SAA treatment. Consequently, the antioxidants seleno-l-methionine and Mn(III) tetrakis-(4-benzoic acid)porphyrin and specific inhibitors for JNK and ERK1/2 effectively blocked the SAA-induced eNOS mRNA decrease and SAA-induced decrease in endothelium-dependent vasorelaxation in porcine coronary arteries. Thus, SAA at clinically relevant concentrations causes endothelial dysfunction in both porcine coronary arteries and HCAECs through molecular mechanisms involving eNOS downregulation, oxidative stress, and activation of JNK and ERK1/2 as well as NF-κB. These findings suggest that SAA may contribute to the progress of coronary artery disease.

Download Full-text

Continuous PTH in Male Mice Causes Bone Loss Because It Induces Serum Amyloid A

Endocrinology ◽

10.1210/en.2018-00265 ◽

2018 ◽

Vol 159 (7) ◽

pp. 2759-2776 ◽

Cited By ~ 6

Author(s):

Shilpa Choudhary ◽

Elizabeth Santone ◽

Sui-Pok Yee ◽

Joseph Lorenzo ◽

Douglas J Adams ◽

...

Keyword(s):

Gene Expression ◽

Bone Marrow ◽

Bone Resorption ◽

Bone Formation ◽

Serum Amyloid A ◽

Serum Amyloid ◽

Human Bone ◽

Human Bone Marrow ◽

Dependent Manner ◽

Amyloid A

Abstract Increased bone resorption is considered to explain why intermittent PTH is anabolic for bone but continuous PTH is catabolic. However, when cyclooxygenase-2 (COX2) is absent in mice, continuous PTH becomes anabolic without decreased resorption. In murine bone marrow stromal cells (BMSCs), serum amyloid A (SAA)3, induced in the hematopoietic lineage by the combination of COX2-produced prostaglandin and receptor activator of nuclear factor κB ligand (RANKL), suppresses PTH-stimulated osteoblast differentiation. To determine whether SAA3 inhibits the anabolic effects of PTH in vivo, wild-type (WT) and SAA3 knockout (KO) mice were infused with PTH. In WT mice, continuous PTH induced SAA3 and was catabolic for bone. In KO mice, PTH was anabolic, increasing trabecular bone, serum markers of bone formation, and osteogenic gene expression. In contrast, PTH increased all measurements associated with bone resorption, as well as COX2 gene expression, similarly in KO and WT mice. SAA1 and SAA2 in humans are likely to have analogous functions to SAA3 in mice. RANKL induced both SAA1 and SAA2 in human bone marrow macrophages in a COX2-dependent manner. PTH stimulated osteogenesis in human BMSCs only when COX2 or RANKL was inhibited. Addition of recombinant SAA1 or SAA2 blocked PTH-stimulated osteogenesis. In summary, SAA3 suppresses the bone formation responses but not the bone resorption responses to PTH in mice, and in the absence of SAA3, continuous PTH is anabolic. In vitro studies in human bone marrow suggest that SAA may be a target for enhancing the therapeutic effects of PTH in treating osteoporosis.

Download Full-text

Serum Amyloid A Aggravates Lipopolysaccharide-Induced Injury of BEAS-2B Cells by Activating Toll-Like Receptor 2/Activator Protein-1 Signaling

Journal of Biomaterials and Tissue Engineering ◽

10.1166/jbt.2021.2557 ◽

2021 ◽

Vol 11 (2) ◽

pp. 282-289

Author(s):

Shiming Yang ◽

Yumei Qin ◽

Li Ding ◽

Jiangbo Wang ◽

Haiqing Zhao

Keyword(s):

Cell Viability ◽

Serum Amyloid A ◽

Serum Amyloid ◽

Epithelial Cell Line ◽

Dependent Manner ◽

Activator Protein 1 ◽

Toll Like Receptor ◽

Concentration Dependent Manner ◽

Amyloid A ◽

Activator Protein

The serum amyloid A (sAA) is a common sensitive indicator for the diagnosis of infectious diseases, and sAA levels are increased in pneumonia. However, the detailed molecular mechanism is unknown. Previous studies have demonstrated the participation of Toll-like receptor (TLR) 2 and its downstream protein activator protein-1 (AP-1) in inflammatory lung injury. This study aimed to investigate the effect of sAA on LPS-induced BEAS-2B cells injury and uncover the possible mechanism. The human bronchial epithelial cell line BEAS-2B was exposed to sAA with or without lipopolysaccharide (LPS) treatment, then cell viability, inflammation and apoptosis were evaluated. The effects of TLR2 knockout on sAA + LPS-treated BEAS-2B cells were also determined. Results revealed that sAA treatment reduced cell viability in a concentration-dependent manner and the effect of 500 nM sAA on cell viability was approximately equivalent to LPS. The levels of inflammatory cytokines including tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-8, monocyte chemotactic protein (MCP)-1 and IL-6 as well as cell apoptosis and expression of proteins related to apoptosis were significantly increased upon sAA or LPS stimulation. The expression of TLR2 and AP-1 was also elevated in cells challenged with sAA or LPS. Besides, sAA and LPS co-treatment further enhanced the actions of LPS. However, the knockdown of TLR2 obviously blunted the effects of LPS and sAA co-treatment on cell viability, inflammation and apoptosis. Taken together, our results revealed that sAA could exert an enhanced effect on LPS-induced BEAS-2B cells injury via promoting TLR2/AP-1 expression.

Download Full-text

Serum amyloid A protein enhances the activity of secretory non-pancreatic phospholipase A2

Biochemical Journal ◽

10.1042/bj3090461 ◽

1995 ◽

Vol 309 (2) ◽

pp. 461-464 ◽

Cited By ~ 45

Author(s):

W Pruzanski ◽

F C de Beer ◽

M C de Beer ◽

E Stefanski ◽

P Vadas

Keyword(s):

Phospholipase A2 ◽

Acute Phase ◽

Serum Amyloid A ◽

Acute Phase Proteins ◽

Lipolytic Activity ◽

Lipoprotein Metabolism ◽

Serum Amyloid ◽

Dependent Manner ◽

Amyloid A ◽

Serum Amyloid A Protein

The acute-phase proteins serum amyloid A protein (SAA) and secretory phospholipase A2 (sPLA2) are simultaneously expressed during inflammatory conditions. SAA associates with high-density lipoprotein (HDL) altering its physicochemical composition. We found that purified acute-phase SAA, but not the constitutive form, markedly enhances the lipolytic activity of sPLA2 in a dose-related manner with phosphatidylcholine/lysophosphatidylcholine or phosphatidylethanolamine/lysophosphatidylethanolamine liposomal substrates. Normal HDL was found to reduce activity of sPLA2 in a dose-dependent manner, but when acute-phase HDL containing 27% SAA was tested, it enhanced sPLA2 activity. Immunopurified monospecific antibodies against SAA completely abolished the enhancing activity of SAA and acute-phase HDL. Given the central role of HDL in lipoprotein metabolism, the interaction between HDL, SAA and sPLA2 may account for changes detected in lipoprotein metabolism during the acute phase.

Download Full-text

Serum Amyloid A is Expressed in the Brain After Traumatic Brain Injury in a Sex-Dependent Manner

Cellular and Molecular Neurobiology ◽

10.1007/s10571-020-00808-3 ◽

2020 ◽

Vol 40 (7) ◽

pp. 1199-1211 ◽

Cited By ~ 1

Author(s):

Sirena Soriano ◽

Bridget Moffet ◽

Evan Wicker ◽

Sonia Villapol

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Serum Amyloid A ◽

Serum Amyloid ◽

Dependent Manner ◽

Amyloid A ◽

The Brain

Download Full-text

Serum amyloid A sequesters diverse phospholipids and their hydrolytic products, hampering fibril formation and proteolysis in a lipid-dependent manner

Chemical Communications ◽

10.1039/c8cc01424h ◽

2018 ◽

Vol 54 (28) ◽

pp. 3532-3535 ◽

Cited By ~ 7

Author(s):

Shobini Jayaraman ◽

Donald L. Gantz ◽

Christian Haupt ◽

Marcus Fändrich ◽

Olga Gursky

Keyword(s):

Serum Amyloid A ◽

Amyloid Fibril ◽

Fibril Formation ◽

Serum Amyloid ◽

Dependent Manner ◽

Amyloid A ◽

Amyloid Fibril Formation

Serum amyloid A can solubilize diverse phospholipids and their hydrolytic products to form lipoprotein nanoparticles, which hampers amyloid fibril formation.

Download Full-text

Serum amyloid A generates high density lipoprotein with cellular lipid in an ABCA1- or ABCA7-dependent manner

The Journal of Lipid Research ◽

10.1194/jlr.m600145-jlr200 ◽

2006 ◽

Vol 47 (7) ◽

pp. 1542-1550 ◽

Cited By ~ 39

Author(s):

Sumiko Abe-Dohmae ◽

Koichi H. Kato ◽

Yoshitaka Kumon ◽

Wei Hu ◽

Hideaki Ishigami ◽

...

Keyword(s):

High Density Lipoprotein ◽

Serum Amyloid A ◽

Density Lipoprotein ◽

High Density ◽

Serum Amyloid ◽

Dependent Manner ◽

Cellular Lipid ◽

Amyloid A

Download Full-text

Human Serum Amyloid A Protein Inhibits Hepatitis C Virus Entry into Cells

Journal of Virology ◽

10.1128/jvi.02627-06 ◽

2007 ◽

Vol 81 (11) ◽

pp. 6128-6133 ◽

Cited By ~ 49

Author(s):

Zhaohui Cai ◽

Lei Cai ◽

Jieyun Jiang ◽

Kyung-Soo Chang ◽

Deneys R. van der Westhuyzen ◽

...

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

Serum Amyloid A ◽

Virus Entry ◽

Immune Defense ◽

Hcv Infection ◽

Serum Amyloid ◽

Dependent Manner ◽

Amyloid A ◽

Serum Amyloid A Protein

ABSTRACT Serum amyloid A (SAA) is an acute-phase protein induced by a variety of inflammatory stimuli, including bacterial and viral infections. SAA was recently found to function as an opsonin for gram-negative bacteria. We report here that SAA inhibited hepatitis C virus (HCV) infection in cultured cells. SAA reduced HCV infectivity in a dose-dependent manner when added during HCV infection but not after virus entry. SAA bound HCV virions and specifically blocked HCV entry but did not affect virus attachment. These findings suggest that SAA functions as part of the host innate immune defense mechanisms against HCV infection in humans.

Download Full-text