Expression of AIM2 is high and correlated with inflammation in hepatitis B virus associated glomerulonephritis

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Abstract

Background & aims

Innate immunity is the first line of defense against invasive microbial infection, and AIM2 plays an important role in this process by sensing double-stranded DNA viruses. However, the role of AIM2 in regulating the immune response to viruses in vivo, especially in sensing hepatitis B virus (HBV), has not been examined. We hypothesized that the expression of AIM2 increases corresponding to HBV-mediated inflammation in patients with hepatitis B virus associated glomerulonephritis (HBV-GN), a condition which activates inflammatory mechanisms and causes renal damage. To test this hypothesis, we analyzed the expression of AIM2 in HBV-GN patients in relation to the inflammatory response to HBV infection.

Methods

A total of 79 patients diagnosed with chronic nephritis (CN) were enrolled in this study, including 54 HBV-GN patients as the experimental group and 24 chronic glomerulonephritis (CGN) patients as the negative control group. Six patients diagnosed with chronic hepatitis B (CHB) were also enrolled as positive controls. Each CN patient received renal biopsy, and immunohistochemistry was used to detect the expression of AIM2 and inflammatory factors caspase-1 and IL-1β in the biopsy specimens. CHB patients received liver puncture biopsy, and immunohistochemistry was used to detect the expression of AIM2 in these specimens. Expression of AIM 2 among different groups and in relation to inflammatory factors caspase-1 and IL-1β was analyzed.

Results

The expression of AIM2 in HBV-GN patients (81.4%) was significantly higher than in CGN patients (4.0%). Among the HBV-GN patients, expression of AIM2 was significantly higher in the high HBV replication group than in the low HBV replication group. AIM2 expression was not correlated with age, gender, HBeAg status in serum, HBV-antigen type deposited in renal tissue or pathological type of HBV-GN. However, AIM2 levels were positively correlated with the expression of caspase-1 and IL-1β in HBV-GN patients. The data suggest that AIM2 expression is directly correlated with HBV infection-associated inflammation.

Conclusion

The elevation of AIM2 during HBV infection or replication may contribute to its associated inflammatory damage, thus providing a putative therapeutic target and a new avenue for researching the pathogenesis of HBV-GN.

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Most cited references 15

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IL-1, IL-18, and IL-33 families of cytokines.

William P Arend, Gaby Palmer, Cem Gabay (2008)

The interleukin-1 (IL-1), IL-18, and IL-33 families of cytokines are related by mechanism of origin, receptor structure, and signal transduction pathways utilized. All three cytokines are synthesized as precursor molecules and cleaved by the enzyme caspase-1 before or during release from the cell. The NALP-3 inflammasome is of crucial importance in generating active caspase-1. The IL-1 family contains two agonists, IL-1alpha and IL-1beta, a specific inhibitor, IL-1 receptor antagonist (IL-1Ra), and two receptors, the biologically active type IL-1R and inactive type II IL-1R. Both IL-1RI and IL-33R utilize the same interacting accessory protein (IL-1RAcP). The balance between IL-1 and IL-1Ra is important in preventing disease in various organs, and excess production of IL-1 has been implicated in many human diseases. The IL-18 family also contains a specific inhibitor, the IL-18-binding protein (IL-18BP), which binds IL-18 in the fluid phase. The IL-18 receptor is similar to the IL-1 receptor complex, including a single ligand-binding chain and a different interacting accessory protein. IL-18 provides an important link between the innate and adaptive immune responses. Newly described IL-33 binds to the orphan IL-1 family receptor T1/ST2 and stimulates T-helper 2 responses as well as mast cells.

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Asian-Pacific consensus statement on the management of chronic hepatitis B: a 2008 update

Yun-Fan Liaw, Nancy Leung, Jia-Horng Kao … (2008)

Large amounts of new data on the natural history and treatment of chronic hepatitis B virus (HBV) infection have become available since 2005. These include long-term follow-up studies in large community-based cohorts or asymptomatic subjects with chronic HBV infection, further studies on the role of HBV genotype/naturally occurring HBV mutations, treatment of drug resistance and new therapies. In addition, Pegylated interferon α2a, entecavir and telbivudine have been approved globally. To update HBV management guidelines, relevant new data were reviewed and assessed by experts from the region, and the significance of the reported findings were discussed and debated. The earlier “Asian-Pacific consensus statement on the management of chronic hepatitis B” was revised accordingly. The key terms used in the statement were also defined. The new guidelines include general management, special indications for liver biopsy in patients with persistently normal alanine aminotransferase, time to start or stop drug therapy, choice of drug to initiate therapy, when and how to monitor the patients during and after stopping drug therapy. Recommendations on the therapy of patients in special circumstances, including women in childbearing age, patients with antiviral drug resistance, concurrent viral infection, hepatic decompensation, patients receiving immune-suppressive medications or chemotherapy and patients in the setting of liver transplantation, are also included.

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Absent in melanoma 2 is required for innate immune recognition of Francisella tularensis.

Jonathan Jones, Nobuhiko Kayagaki, Petr Broz … (2010)

Macrophages respond to cytosolic nucleic acids by activating cysteine protease caspase-1 within a complex called the inflammasome. Subsequent cleavage and secretion of proinflammatory cytokines IL-1beta and IL-18 are critical for innate immunity. Here, we show that macrophages from mice lacking absent in melanoma 2 (AIM2) cannot sense cytosolic double-stranded DNA and fail to trigger inflammasome assembly. Caspase-1 activation in response to intracellular pathogen Francisella tularensis also required AIM2. Immunofluorescence microscopy of macrophages infected with F. tularensis revealed striking colocalization of bacterial DNA with endogenous AIM2 and inflammasome adaptor ASC. By contrast, type I IFN (IFN-alpha and -beta) secretion in response to F. tularensis did not require AIM2. IFN-I did, however, boost AIM2-dependent caspase-1 activation by increasing AIM2 protein levels. Thus, inflammasome activation was reduced in infected macrophages lacking either the IFN-I receptor or stimulator of interferon genes (STING). Finally, AIM2-deficient mice displayed increased susceptibility to F. tularensis infection compared with wild-type mice. Their increased bacterial burden in vivo confirmed that AIM2 is essential for an effective innate immune response.

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Author and article information

Contributors

Wenjun Du

Junhui Zhen

Zhaomin Zheng

Shumin Ma

Shijun Chen

Journal

Journal ID (nlm-ta): J Inflamm (Lond)

Journal ID (iso-abbrev): J Inflamm (Lond)

Title: Journal of Inflammation (London, England)

Publisher: BioMed Central

ISSN (Electronic): 1476-9255

Publication date Collection: 2013

Publication date (Electronic): 10 December 2013

Volume: 10

Page: 37

Affiliations

[1 ]Shandong University School of Medicine, Jinan, China

[2 ]Digestive Department, Shandong provincial Qianfoshan hospital, Shandong University, Jinan, China

[3 ]Department of Pathology, Shandong University School of Medicine, Jinan, China

[4 ]Department of Liver Disease, Jinan Infectious Disease Hospital, Shandong University School of Medicine, Jinan, China

Article

Publisher ID: 1476-9255-10-37

DOI: 10.1186/1476-9255-10-37

PMC ID: 4028891

PubMed ID: 24325587

SO-VID: c41d785b-f161-42f8-8929-c8aa66aed438

License:

This is an open access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Expression of AIM2 is high and correlated with inflammation in hepatitis B virus associated glomerulonephritis

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Abstract

Background & aims

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Most cited references 15

IL-1, IL-18, and IL-33 families of cytokines.

Asian-Pacific consensus statement on the management of chronic hepatitis B: a 2008 update

Absent in melanoma 2 is required for innate immune recognition of Francisella tularensis.

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