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Serum amyloid A induces mitogenic signals in regulatory T cells via monocyte activation.

ABSTRACT: Serum amyloid A (SAA) has recently been identified by our group as a mitogen for regulatory T cells (Treg). However, the molecular mechanism by which SAA induces Treg proliferation is unknown. Here we provide evidence that IL-1? and IL-6 are directly involved in the SAA-mediated proliferation of Treg. By engaging its several cognate receptors, SAA induces IL-1? and IL-6 secretion by monocytes and drives them toward an HLA-DR(hi) HVEM(lo) phenotype resembling immature dendritic cells, which have been implicated in tolerance generation. This monocyte-derived cytokine milieu is required for Treg expansion, as inhibition of IL-1? and IL-6 abrogate the ability of SAA to induce Treg proliferation. Furthermore, both IL-1? and IL-6 are required for ERK1/2 and AKT signaling in proliferating Treg. Collectively, these results point to a novel mechanism, by which SAA initiates a monocyte-dependent process that drives mitogenic signals in Treg.

SUBMITTER: Nguyen KD

PROVIDER: S-EPMC4068397 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature

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Serum amyloid A induces mitogenic signals in regulatory T cells via monocyte activation.

Nguyen Khoa D KD Macaubas Claudia C Truong Phi P Wang Nan N Hou Tieying T Yoon Taejin T Mellins Elizabeth D ED

Molecular immunology 20140313 2

Serum amyloid A (SAA) has recently been identified by our group as a mitogen for regulatory T cells (Treg). However, the molecular mechanism by which SAA induces Treg proliferation is unknown. Here we provide evidence that IL-1β and IL-6 are directly involved in the SAA-mediated proliferation of Treg. By engaging its several cognate receptors, SAA induces IL-1β and IL-6 secretion by monocytes and drives them toward an HLA-DR(hi) HVEM(lo) phenotype resembling immature dendritic cells, which have ...[more]

PMID: 24632292

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Project description:Serum amyloid A (SAA) proteins are acute-phase reactant associated with high-density lipoprotein (HDL) particles and increase in the plasma 1000-fold during inflammation. Recent studies have implicated SAAs in innate immunity and various disorders; however, the precise mechanism eludes us. Previous studies have shown SAAs are elevated following stroke and cerebral ischemia, and our studies demonstrated that SAA-deficient mice reduce inflammation and infarct volumes in a mouse stroke model. Our studies demonstrate that SAA increases the cytokine interleukin-1? (IL-1?), which is mediated by Nod-like receptor protein 3 (NLRP3) inflammasome, cathepsin B, and caspase-1 and may play a role in the pathogenesis of neurological disorders. SAA induced the expression of NLRP3, which mediated IL-1? induction in murine BV-2 cells and both sex primary mouse microglial cells, in a dose- and time-dependent fashion. Inhibition or KO of the NLRP3 in microglia prevented the increase in IL-1?. N-acetyl-l-cysteine and mito-TEMPO blocked the induction of IL-1? by inhibiting ROS with SAA treatment. In addition, inhibition of cathepsin B with different drugs or microglia from CatB-deficient mice attenuated inflammasome activation. Our studies suggest that the impact of SAA on inflammasome stimulation is mediated in part by the receptor for advanced glycation endproducts and Toll-like receptor proteins 2 and 4. SAA induced inflammatory cytokines and an M1 phenotype in the microglial cells while downregulating anti-inflammation M2 phenotype. These studies suggest that brain injury to can elicit a systemic inflammatory response mediated through SAA that contributes to the pathological outcomes.SIGNIFICANCE STATEMENT In the present study, serum amyloid A can induce that activation of the inflammasome in microglial cells and give rise to IL-1? release, which can further inflammation in the brain following neurological diseases. The also presents a novel target for therapeutic approaches in stroke.

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Serum amyloid A induces mitogenic signals in regulatory T cells via monocyte activation.

Publications

Serum amyloid A induces mitogenic signals in regulatory T cells via monocyte activation.

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