AIM2 was first reported to act as a putative tumor suppressor in malignant melanoma [
11]. Recent research demonstrated that AIM2 plays an important role in the innate immune response through sensing potentially dangerous cytoplasmic ds-DNA and inducing the formation of the ASC inflammasome, which then induces the activation of caspase-1 and release of mature IL-1β [
7]. Maturation and secretion of IL-1β, an important intracellular cytokine belonging to the IL-1 superfamily [
12], ultimately leads to tissue damage [
13]. As a non-specific receptor for cytoplasmic DNA, AIM2 can be activated by and bind to plasmid DNA, DNA from the bacterium
Listeria monocytogenes and even synthetic ds-DNA [
14]. Previous research detected AIM2 in the small intestine, spleen, peripheral white blood cells and testis [
15]. Our study describes the inducible expression of AIM2 in liver and kidney tissue and the exclusive expression of AIM2 in the hepatic cytoplasm and glomerular endothelial cell and mesangial cell cytoplasm in the kidney. These results further suggest that AIM2 may play an important inflammatory role in not only HBV-GN but also CHB and may provide a new avenue for researching the pathogenesis of CHB. We found that the positive expression rate of AIM2 in the HBV-GN group was significantly higher than that of the CGN group. As neither age nor gender were statistically different between the two groups, this suggests that there is indeed a relationship between chronic HBV infection and AIM2 elevation. We also considered another potential influence factor, HBeAg status in serum, which may have contributed to the mutation of the HBV-DNA-P-BCP (basal core promoter) or pre-C region, influencing AIM2 activation and binding to HBV-DNA. Our results showed that the expression of AIM2 was not significantly different between the HBeAg positive and negative groups, demonstrating that AIM2 activation and binding to HBV-DNA is not influenced by serum HBeAg status. Moreover, our results indicated that the positive expression rate of AIM2 in the high replication group (HBV-DNA ≥ 1 × 10
5 copies/ml) was significantly higher than that of the low replication group (HBV-DNA < 1 × 10
5 copies/ml), suggesting that high HBV load led to the increase in AIM2 expression. A recent study focusing on the relationship between AIM2 expression and acute and chronic hepatitis B infection showed that AIM2 mRNA expression was negatively correlated with serum HBV load [
16]. This study included acute hepatitis B (AHB) and chronic hepatitis B (CHB) patients. The pathogenesis of AHB and CHB is widely accepted to be high HBV load assault and immune injury, respectively, though the pathogenesis of each in the study was unclear. For both AHB and CHB, only inflammation (i.e., immune injury) was noted. The role of AIM2 in regulating the immune response to viral infection can hereby be emphasized. A higher HBV load provides a greater opportunity to bind AIM2 and lead, subsequently, to activation of the inflammation signal pathway. However, some of the CHB patients in the characteristic stages of immune tolerance, immune clearance, inactive-carrier and reactivation in this study exhibited no inflammation. In our present study, all HBV-GN patients exhibited inflammation. Moreover, the pathogenesis of CHB and HBV-GN is different. As for the role of HBV in HBV-GN pathogenesis, it needs to be explored further. Previous research reported that high HBV-DNA load was correlated with HBV-GN-related morbidity [
4]; however, the specific pathogenesis for this has been unclear until now. Our results have demonstrated that this morbidity may be due to the high HBV-DNA load of these patients having a greater chance to activate AIM2, resulting in the release of inflammatory cytokines and subsequent renal damage.
Several HBV antigens, including HBsAg and HBcAg, have been found deposited in the glomerulus and thought to contribute to the pathogenesis of HBV-GN [
17]. Our data indicate that the expression of AIM2 is not correlated with the type of HBV-antigen deposited in nephridial tissue, suggesting also that AIM2 binding to HBV-DNA was not dependent on HBV-antigen type deposited. Previous research demonstrated that different pathological types of HBV-GN have different clinical outcomes [
18], so we further analyzed the expression of AIM2 among various pathological types within the HBV-GN group. The results demonstrated that the expression of AIM2 was not affected by these various pathological types of HBV-GN, suggesting that inflammation due to AIM2 activation commonly exists irrespective of pathological type.
IL-1β is an important intracellular cytokine which binds to receptors and activates the downstream NF-ĸB signaling pathway, releasing inflammatory factors that cause tissue damage. Our results showed that the expression of AIM2 was positively correlated with the expression of caspase-1 and IL-1β in HBV-GN. HBV particles were detectable using scanning electron microscopy in nephridial tissue from HBV-GN patients [
4]. During the innate immune response to invading HBV, activated AIM2 may bind to ASC, inducing activation of caspase-1 and releasing IL-1β [
7]. Similar results were obtained in the recent Wu study focusing on the relationship between AIM2 expression and acute and chronic hepatitis B infection [
16], suggesting that AIM2 plays an important role in both HBV-GN and hepatitis B infection. As long as HBV is present, AIM2 may be activated and lead to subsequent inflammatory injury. Our study further confirms this mode of signal transduction. Within the experimental group, the expression level of AIM2 was positively correlated with the level of caspase-1, and the level of caspase-1 was positively correlated with the level of IL-1β, suggesting that this inflammation signal transfer pathway was related to AIM2 levels in HBV-GN and, subsequently, that AIM2 may play an important role in the pathogenesis of HBV-GN.
In summary, we found the expression of AIM2 to be significantly increased in HBV-GN patients. AIM2 levels were highly correlated with HBV load and inflammation in HBV-GN. Collectively, these results suggest that the elevation of AIM2 during HBV infection or replication may contribute to renal damage due to inflammation. Our findings may help provide a new therapeutic target for HBV-GN and a new avenue for researching its pathogenesis.