Microbial regulation of SAA3 expression in mouse colon and adipose tissue

Reigstad, Christopher S.; Bäckhed, Fredrik

doi:10.4161/gmic.1.1.10514

Cited by 19 publications

(20 citation statements)

References 26 publications

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“…The expression of isoforms SAA1 and 2 occurs mainly in the liver under the stimuli of proinflammatory cytokines such as IL-6, IL-1, and TNF-a and is subsequently released into the blood during the acute phase response, where they associate with HDL particles. In contrast, SAA3 in mice has been shown to be expressed in a wide variety of cells and tissues, including leukocytes and epithelium, and has never been identified bound to HDL [34], but rather appears to have autocrine or paracrine effects [35,36]. In fact, it has been demonstrated that following exposure to different stimuli, such as oropharyngeal administration of LPS, and airway epithelial-specific NF-jB activation, lungs of C57BL/6 mice exhibit a preferential mRNA induction of SAA3 over SAA1 or SAA2 [37].…”

Section: Discussionmentioning

confidence: 94%

Herpes simplex virus type 1 induces simultaneous activation of Toll-like receptors 2 and 4 and expression of the endogenous ligand serum amyloid A in astrocytes

Villalba

Hott

Martin

et al. 2012

Med Microbiol Immunol

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Herpes simplex virus type 1 (HSV-1) is the most common pathogenic cause of sporadic acute encephalitis and it produces latent persistent infection lifelong in infected individuals. Brain inflammation is associated with activation of glial cells, which can detect pathogen-associated molecular patterns (PAMPs) through a variety of pattern-recognition receptors (PRR), including Toll-like receptors (TLRs). In this study, we evaluated the expression and activation of TLR2, TLR3, and TLR4 in HSV-1-infected astrocyte and neuronal primary cultures. Our results showed a clear induction in TLR2 and TLR4 expression in astrocytes as early as 1 h after HSV-1 infection, whereas no significant change was observed in neurons. In addition, infected astrocytes showed increased levels of interferon regulatory factors IRF3 and IRF7, interferon β (INFβ), interleukin 6 (IL6), and serum amyloid A (SAA3) transcripts, as well as phospho-IRF3 protein. These effects seemed to be dependent on viral replication since previous treatment of the cells with acyclovir resulted in low levels of TLRs expression and activation even after 4 h post-infection. These results suggest that reactivation of HSV-1 at the central nervous system (CNS) would likely induce and activate TLR2 and TLR4 receptors directly through interaction of astrocytes with the pathogen and also indirectly by endogenous ligands produced locally, such as serum amyloid protein, potentiating the neuroinflammatory response.

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Section: Discussionmentioning

confidence: 94%

Herpes simplex virus type 1 induces simultaneous activation of Toll-like receptors 2 and 4 and expression of the endogenous ligand serum amyloid A in astrocytes

Villalba

Hott

Martin

et al. 2012

Med Microbiol Immunol

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“… 11 , 12 , 14 , 15 Human SAA1, 2 is comparable to mouse SAA3 in structure, function, and distribution. 11 , 16 , 17 Despite genetic similarities of SAA1, 2 between species, the amino acid compositions of human SAA1, 2 protein has greater identity to mouse SAA3 (73%) protein than mouse SAA1, 2 (68%) protein. 11 , 18 In addition to dissemination by the systemic circulation, human and mouse SAA isoforms are locally produced at inflammatory sites.…”

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confidence: 99%

Serum amyloid A and inflammation in diabetic kidney disease and podocytes

Anderberg

Meek

Hudkins

et al. 2015

Laboratory Investigation

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Inflammatory pathways are central mechanisms in diabetic kidney disease (DKD). Serum amyloid A (SAA) is increased by chronic inflammation, but SAA has not been previously evaluated as a potential DKD mediator. The aims of this study were to determine whether SAA is increased in human DKD and corresponding mouse models and to assess effects of SAA on podocyte inflammatory responses. SAA was increased in the plasma of people with DKD characterized by overt proteinuria and inversely correlated with estimated glomerular filtration rate (creatinine-based CKD-EPI). SAA was also elevated in plasma of diabetic mouse models including type 1 diabetes (streptozotocin/C57BL/6) and type 2 diabetes (BTBR-ob/ob). SAA mRNA (Nephromine) was increased in human DKD compared with non-diabetic and/or glomerular disease controls (glomerular fold change 1.5, P=0.017; tubulointerstitium fold change 1.4, P=0.021). The kidneys of both diabetic mouse models also demonstrated increased SAA mRNA (quantitative real-time PCR) expression compared with non-diabetic controls (type 1 diabetes fold change 2.9; type 2 diabetes fold change 42.5, P=0.009; interaction by model P=0.57). Humans with DKD and the diabetic mouse models exhibited extensive SAA protein deposition in the glomeruli and tubulointerstitium in similar patterns by immunohistochemistry. SAA localized within podocytes of diabetic mice. Podocytes exposed to advanced glycation end products, metabolic mediators of inflammation in diabetes, increased expression of SAA mRNA (fold change 15.3, P=0.004) and protein (fold change 38.4, P=0.014). Podocytes exposed to exogenous SAA increased NF-κB activity, and pathway array analysis revealed upregulation of mRNA for NF-κB-dependent targets comprising numerous inflammatory mediators, including SAA itself (fold change 17.0, P=0.006). Inhibition of NF-κB reduced these pro-inflammatory responses. In conclusion, SAA is increased in the blood and produced in the kidneys of people with DKD and corresponding diabetic mouse models. Podocytes are likely to be key responder cells to SAA-induced inflammation in the diabetic kidney. SAA is a compelling candidate for DKD therapeutic and biomarker discovery.

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“…These studies indicate that increased levels of endotoxin exposure, from Western diet-induced microbiota outgrowth, may alter the tolerance threshold, leading to systemic inflammation, decreased glucose tolerance, and poor responses to infection. Expression of SAA3 in the gut is regulated by the microbiome [ 45 ], and SAA3 can bind directly to bacteria, leading to the possibility that SAA3 functions to regulate homeostatic, tolerogenic signaling of endotoxin produced by commensal microbiota. Further investigation is also required to determine whether the generation of immunometabolic imbalance observed in the adipose-resident leukocytes in SAA3-/- mice is due to the absence of SAA3 in the bone marrow during hematopoiesis, or an effect exerted systemically by the secretion of pro-inflammatory mediators from the adipocytes themselves.…”

Section: Discussionmentioning

confidence: 99%

Serum amyloid A3 is required for normal weight and immunometabolic function in mice

Ather

Poynter

2018

PLoS ONE

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Serum amyloid A (SAA) is an apolipoprotein that is robustly upregulated in numerous inflammatory diseases and has been implicated as a candidate pro-inflammatory mediator. However, studies comparing endogenous SAAs and recombinant forms of the acute phase protein have generated conflicting data on the function of SAA in immunity. We generated SAA3 knockout mice to evaluate the contribution of SAA3 to immune-mediated disease, and found that mice lacking SAA3 develop adult-onset obesity and metabolic dysfunction along with defects in innate immune development. Mice that lack SAA3 gain more weight, exhibit increased visceral adipose deposition, and develop hepatic steatosis compared to wild-type littermates. Leukocytes from the adipose tissue of SAA3-/- mice express a pro-inflammatory phenotype, and bone marrow derived dendritic cells from mice lacking SAA3 secrete increased levels of IL-1β, IL-6, IL-23, and TNFα in response to LPS compared to cells from wild-type mice. Finally, BMDC lacking SAA3 demonstrate an impaired endotoxin tolerance response and inhibited responses to retinoic acid. Our findings indicate that endogenous SAA3 modulates metabolic and immune homeostasis.

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Microbial regulation of SAA3 expression in mouse colon and adipose tissue

Cited by 19 publications

References 26 publications

Herpes simplex virus type 1 induces simultaneous activation of Toll-like receptors 2 and 4 and expression of the endogenous ligand serum amyloid A in astrocytes

Herpes simplex virus type 1 induces simultaneous activation of Toll-like receptors 2 and 4 and expression of the endogenous ligand serum amyloid A in astrocytes

Serum amyloid A and inflammation in diabetic kidney disease and podocytes

Serum amyloid A3 is required for normal weight and immunometabolic function in mice

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