Infiltration of M1, but not M2, macrophages is impaired after unilateral ureter obstruction in Nrf2-deficient mice

Chronic inflammation can be a major driver of the failure of a variety of organs, including chronic kidney disease (CKD). The NLR family pyrin domain-containing 3 (NLRP3) inflammasome has been shown to play a pivotal role in inflammation in a mouse kidney disease model. Nuclear factor erythroid 2-related factor 2 (Nrf2), the master transcription factor for anti-oxidant responses, has also been implicated in inflammasome activation under physiological conditions. However, the mechanism underlying inflammasome activation in CKD remains elusive. Here, we show that the loss of Nrf2 suppresses fibrosis and inflammation in a unilateral ureter obstruction (UUO) model of CKD in mice. We consistently observed decreased expression of inflammation-related genes NLRP3 and IL-1β in Nrf2-deficient kidneys after UUO. Increased infiltration of M1, but not M2, macrophages appears to mediate the suppression of UUO-induced CKD symptoms. Furthermore, we found that activation of the NLRP3 inflammasome is attenuated in Nrf2-deficient bone marrow–derived macrophages. These results demonstrate that Nrf2-related inflammasome activation can promote CKD symptoms via infiltration of M1 macrophages. Thus, we have identified the Nrf2 pathway as a promising therapeutic target for CKD

In Situ Delivery and Production System (iDPS) of Anti-Cancer Molecules with Gene-Engineered Bifidobacterium

To selectively and continuously produce anti-cancer molecules specifically in malignant tumors, we have established an in situ delivery and production system (iDPS) with Bifidobacterium as a micro-factory of various anti-cancer agents. By focusing on the characteristic hypoxia in cancer tissue for a tumor-specific target, we employed a gene-engineered obligate anaerobic and non-pathogenic bacterium, Bifidobacterium, as a tool for systemic drug administration. This review presents and discusses the anti-tumor effects and safety of the iDPS production of numerous anti-cancer molecules and addresses the problems to be improved by directing attention mainly to the hallmark vasculature and so-called enhanced permeability and retention effect of tumors

Short-chain fatty acids bind to apoptosis-associated speck-like protein to activate inflammasome complex to prevent Salmonella infection

Short-chain fatty acids (SCFAs) produced by gastrointestinal microbiota regulate immune responses, but host molecular mechanisms remain unknown. Unbiased screening using SCFA-conjugated affinity nanobeads identified apoptosis-associated speck-like protein (ASC), an adaptor protein of inflammasome complex, as a noncanonical SCFA receptor besides GPRs. SCFAs promoted inflammasome activation in macrophages by binding to its ASC PYRIN domain. Activated inflammasome suppressed survival of Salmonella enterica serovar Typhimurium (S. Typhimurium) in macrophages by pyroptosis and facilitated neutrophil recruitment to promote bacterial elimination and thus inhibit systemic dissemination in the host. Administration of SCFAs or dietary fibers, which are fermented to SCFAs by gut bacteria, significantly prolonged the survival of S. Typhimurium–infected mice through ASC-mediated inflammasome activation. SCFAs penetrated into the inflammatory region of the infected gut mucosa to protect against infection. This study provided evidence that SCFAs suppress Salmonella infection via inflammasome activation, shedding new light on the therapeutic activity of dietary fiber. This study shows that short-chain fatty acids (SCFAs) bind to the inflammasome adaptor protein, apoptosis-associated speck-like protein (ASC). SCFAs thereby promote inflammasome activation in macrophages and protect against Salmonella infection via bacterial elimination in gut, shedding new light on the therapeutic activity of dietary fiber

Involvement of caspase-9 and gap junctions on ASC-dependent apoptosis at a high cell density.

<p>(A) Relative mRNA expressions of the NF-κB-regulated genes IL-1β and XIAP were evaluated by quantitative RT-PCR at both low and high cell densities (n = 4 for each). (B) Effects of caspase inhibitors on ASC-dependent apoptosis as evaluated by relative GFP-positive ratio at a high cell density. Z-VAD-fmk; pan-caspase inhibitor, z-YVAD-fmk; caspase-1 inhibitor, Z-LEHD-fmk; caspase-9 inhibitor (n = 4 for each). (C) Activation of caspase-9 induced by ASC introduction as detected by Western blotting at low and high cell densities. (D) Relative mRNA expression of connexin 43 evaluated by quantitative RT-PCR at both low and high cell densities (n = 3 for each). (E) Effect of the gap junction inhibitor CBX on relative GFP-positive ratio at a high cell density (n = 4). (F) Effects of CBX on the activation of caspase-9 at a high cell density by Western blotting. (G) Confirmation of connexin 43 (Cx 43) silencing performed by quantitative RT-PCR (n = 3). And effects of connexin 43 silencing on the activation of caspase-9 at high cell density by Western blotting. Representative results of triplicate experiments. **p<0.01.</p