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Overexpression of hepatic serum amyloid A1 in mice increases IL-17-producing innate immune cells and decreases bone density.

ABSTRACT: Serum amyloid A (SAA) is an acute-phase protein produced primarily in the liver that plays a key role in both the initiation and maintenance of inflammation. Rapidly secreted SAA induces neutrophilia at inflammatory sites, initiating inflammation and inducing the secretion of various cytokines, including TNF-α, IL-6, and IL-17. IL-17 is expressed in several inflammatory cells, including innate immune cells such as γδT cells, ILC3 cells, and neutrophils. Increased IL-17 levels exacerbate various inflammatory diseases. Among other roles, IL-17 induces bone loss by increasing receptor activator of nuclear factor-κB ligand (RANKL) secretion, which stimulates osteoclast differentiation. Several studies have demonstrated that chronic inflammation induces bone loss, suggesting a role for SAA in bone health. To test this possibility, we observed an increase in IL-17-producing innate immune cells, neutrophils, and γδT cells in these mice. In 6-month-old animals, we detected increased osteoclast-related gene expression and IL-17 expression in bone lysates. We also observed an increase in neutrophils that secreted RANKL in the bone marrow of TG mice. Finally, we demonstrated decreased bone mineral density in these transgenic (TG) mice. Our results revealed that the TG mice have increased populations of IL-17-producing innate immune cells, γδT cells, and neutrophils in TG mice. We additionally detected increased RANKL and IL-17 expression in the bone marrow of 6-month-old TG mice. Furthermore, we confirmed significant increases in RANKL-expressing neutrophils in TG mice and decreased bone mineral density. Our results provide evidence that chronic inflammation induced by SAA1 causes bone loss via IL-17-secreting innate immune cells.

SUBMITTER: Choi M

PROVIDER: S-EPMC8086136 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Liver fibrosis is a severe global health problem. However, no effective antifibrotic drugs have been approved. Surf4 is primarily located in the endoplasmic reticulum (ER) and mediates the transport of secreted proteins from the ER to the Golgi apparatus. Knockout of hepatic Surf4 (Surf4 LKO) in mice impairs very-low-density lipoprotein secretion without causing overt liver damage. Here, we found that collagen levels are significantly reduced in the liver of Surf4 LKO mice compared with control Surf4 flox mice, as demonstrated by proteomics, Western blot, and quantitative reverse transcription polymerase chain reaction. Therefore, this study aims to investigate whether and how hepatic Surf4 affects liver fibrosis. We observed that CCl4-induced liver fibrosis is significantly lower in Surf4 LKO mice than in Surf4 flox mice. Mechanistically, hepatic Surf4 deficiency reduces serum amyloid A1 (SAA1) secretion and hepatic stellate cell (HSC) activation. Surf4 coimmunoprecipitates and colocalizes with SAA1. Lack of hepatic Surf4 significantly reduces SAA1 secretion from hepatocytes, and SAA1 activates cultured human HSCs (LX-2 cells). Conditioned medium (CM) from Surf4-deficient primary hepatocytes activates LX-2 cells to a much lesser extent than CM from Surf4 flox primary hepatocytes, and this reduced effect is restored by the addition of recombinant SAA1 to CM from Surf4-deficient hepatocytes. Knockdown of SAA1 in primary hepatocytes or TLR2 in LX-2 cells significantly reduces LX-2 activation induced by CM from Surf4 flox hepatocytes but not from Surf4 LKO hepatocytes. Furthermore, knockdown of SAA1 significantly ameliorates liver fibrosis in Surf4 flox mice but does not further reduce liver fibrosis in Surf4 LKO mice. We also observe substantial expression of Surf4 and SAA1 in human fibrotic livers. Therefore, hepatic Surf4 facilitates SAA1 secretion, activates HSCs, and aggravates liver fibrosis, suggesting that hepatic Surf4 and SAA1 may serve as treatment targets for liver fibrosis.

Project description:BACKGROUND:IL-17 plays a pathogenic role in asthma. ST2- inflammatory group 2 innate lymphoid cells (ILC2s) driven by IL-25 can produce IL-17, whereas ST2+ natural ILC2s produce little IL-17. OBJECTIVE:We characterized ST2+IL-17+ ILC2s during lung inflammation and determined the pathogenesis and molecular regulation of ST2+IL-17+ ILC2s. METHODS:Lung inflammation was induced by papain or IL-33. IL-17 production by lung ILC2s from wild-type, Rag1-/-, Rorcgfp/gfp, and aryl hydrocarbon receptor (Ahr)-/- mice was examined by using flow cytometry. Bone marrow transfer experiments were performed to evaluate hematopoietic myeloid differentiation primary response gene-88 (MyD88) signaling in regulating IL-17 production by ILC2s. mRNA expression of IL-17 was analyzed in purified naive ILC2s treated with IL-33, leukotrienes, and inhibitors for nuclear factor of activated T cells, p38, c-Jun N-terminal kinase, or nuclear factor ? light-chain enhancer of activated B cells. The pathogenesis of IL-17+ ILC2s was determined by transferring wild-type or Il17-/- ILC2s to Rag2-/-Il2rg-/- mice, which further induced lung inflammation. Finally, expression of 106 ILC2 signature genes was compared between ST2+IL-17+ ILC2s and ST2+IL-17- ILC2s. RESULTS:Papain or IL-33 treatment boosted IL-17 production from ST2+ ILC2s (referred to by us as ILC217s) but not ST2- ILC2s. Ahr, but not retinoic acid receptor-related orphan receptor ?t, facilitated the production of IL-17 by ILC217s. The hematopoietic compartment of MyD88 signaling is essential for ILC217 induction. IL-33 works in synergy with leukotrienes, which signal through nuclear factor of activated T-cell activation to promote IL-17 in ILC217s. Il17-/- ILC2s were less pathogenic in lung inflammation. ILC217s concomitantly expressed IL-5 and IL-13 but expressed little GM-CSF. CONCLUSION:During lung inflammation, IL-33 and leukotrienes synergistically induce ILC217s. ILC217s are a highly pathogenic and unexpected source for IL-17 in lung inflammation.

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Overexpression of hepatic serum amyloid A1 in mice increases IL-17-producing innate immune cells and decreases bone density.

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