Immune response

11 Nov 2014 NUS professors have identified SAG (sensitive to apoptosis gene) to have a key role in inflammatory responses, facilitating macrophage survival during early infection.

Macrophages are at the frontline of immune defense. Macrophages recognize and kill the invading microbe. It generates inflammatory response to alert the host of the presence of pathogens. Therefore macrophage survival in the early phase of infection is critical for host survival. In the course of infection, macrophages may undergo apoptosis as an optimal strategy against severe microbial infection. However, the mechanism of switching between apoptosis and immune response is under-explored. A team led by Prof DING Jeak Ling from the Department of Biological Sciences in NUS has shown that ubiquitination by SAG-UPS (sensitive to apoptosis gene ubiquitin-proteasome system) confers survival advantage to the macrophages during early infection. Ubiquitination regulates degradation of cellular proteins, controlling a protein’s half-life. They have demonstrated that SAG plays a key regulatory role in balancing the ratio of pro- and anti- apoptotic factors in the infected macrophages. SAG-knockdown significantly reduced the ubiquitination of Bax and SARM (sterile alpha and HEAT/armadillo-motif-containing protein), stabilizing these pro-apoptotic factors and leading to intrinsic apoptosis. In contrast, under chronic infection-inflammation condition, macrophages overexpress SAG, leading to upregulation of pro-tumorigenic cytokines, and downregulation of anti-tumorigenic and anti-inflammatory. Altogether, their findings identified SAG as a survival determinant for macrophages, as well as a modulator in manipulating timely immune response.

They have also identified SAG to be a survival determinant for macrophages under infection. SAG-UPS is a key switch between life and death (by apoptosis) and immune response OR immune-overactivation and tumorigenesis.

The potency of SAG-UPS suggests it to be a potential target for developing immunomodulatory therapeutics against autoimmunity, immunodeficiency diseases and cancer. Future work using animal models with transient/conditional SAG knockdown may help to evaluate the impact of SAG responses on infection, disease progression and its potential contribution to the recruitment of immune cells to a tumor microenvironment under chronic infection (see Figure).

The team’s observation of SAG-mediated upregulation of protumorigenic indicates that SAG has a key role in inflammatory responses, facilitating macrophage survival during early infection. Supporting their finding are recent studies using an inhibitor of neddylation, which reduced the production by dendritic cells. Recent studies using SAG deletion further highlighted the critical role of SAG in tumorigenesis and tumor angiogenesis. These interesting findings lend credence to their observation of the upregulation of protumorigenic cytokines, when immune cells undergo SAG overexpression. Corroboratively, these cytokines have also been referred to as proangiogenic cytokines.

This figure shows a hypothetical mechanism of action of SAG-UPS upon infection. SAG-UPS maintains macrophage survival signal to facilitate immune response against infection at the early phase. SAG-mediated ubiquitination of cytosolic Bax and SARM is upregulated rapidly, thus sequestering these pro-apoptotic factors away from the mitochondria. However, continuously over-activated ubiquitination by SAG may induce uncontrolled survival signals in macrophages. Chronic infection-inflammation condition may over-activate macrophages to produce pro-tumorigenic cytokines, which may create a pro-tumorigenic microenvironment, favoring proliferation of over-activated immune cells, causing them to switch into a tumorigenic mode. [Image credit: CHANG Shu-Chun and DING Jeak Ling]

Reference

Chang SC, Ding JL. ”Ubiquitination by SAG regulates macrophage survival/death and immune response during infection.” Cell Death & Differentiation. 21 (2014) 1388.