Sepsis and the Stroma
Sepsis is a complex inflammatory response that arises from a systemic infection and can cause long-term morbidity or mortality. Several different innate immune genes have been linked to sepsis progression, and a previous study identified a deleterious role for the transcription factor IFN regulatory factor 3 (IRF3). In this Top Read, Heipertz et al. (p. 398) show that IRF3 knockout (KO) mice were protected from moderate sepsis induced by the cecal ligation and puncture (CLP) model that included treatment with antibiotics and lactated Ringer solution. Examination of peritoneal cells revealed reduced phagocytosis in wild-type mice compared with IRF3-KO mice following CLP, and a reduction in phagocytosis correlated with disease severity. Computational modeling indicated that the presence of IRF3 was associated with greater complexity and different dynamics in the network of inflammatory mediators measured in the sera. Studies with bone marrow chimeras discerned a role for the stromal compartment but not the leukocyte compartment in mediating sepsis pathogenesis by modulating IL-6 production by monocytes. Taken together, these results define a role for IRF3 in stromal cells that drives the pathogenesis of sepsis via IL-6–dependent inflammatory pathways.
Adenovirus Vector Adverse Events
Adenovirus (Ad) vectors are used for gene therapy because of their high transduction rate, but preclinical studies have shown that hepatotoxicity can be an adverse event following Ad administration. In this Top Read, Shimizu et al. (p. 410) examine the mechanism associated with early-phase hepatotoxicity using a conventional Ad-CAL2 vector or a modified Ad-E4-122aT-CAL2 that includes the liver-specific miR-122a, which can limit leaky Ad gene expression in the liver. They measured hepatoxicity by examining serum alanine aminotransferase (ALT) levels, liver histopathology, and expression levels of apoptosis-related genes 48 h after Ad vector administration. The Ad-CAL2 vector was associated with greater hepatotoxicity at this early time and was less severe in mice given Ad-E4-122aT-CAL2, but hepatic cytokine expression was similar for both vectors. Treatment of mouse hepatocytes with Ad-CAL2, but not Ad-E4-122aT-CAL2, was associated with IL-6 induction and leaky Ad gene expression, which contributed to cytotoxicity. However, treatment with a JAK/STAT inhibitor reduced IL-6 production and subsequent cytotoxicity in hepatocytes. In addition, administration of Ad-CAL2 to IL-6 KO mice was associated with a reduction in leaky Ad gene expression and hepatotoxicity during the early phase. These findings reveal a role for leaky Ad gene expression in contributing to early-phase hepatotoxicity and suggest that modification of Ad vectors, as seen with Ad-E4-122aT-CAL2, can reduce this side effect.
A BET against Arthritis
Rheumatoid arthritis (RA) is an autoimmune disorder associated with joint inflammation and tissue destruction that is caused by infiltration of immune cells and proliferation of fibroblast-like synoviocytes (FLS). In this Top Read, Krishna et al. (p. 422) examine the effects of a bromodomain and extra terminal (BET) domain family inhibitor, JQ1, on RA-FLS. Treatment of RA-FLS with the active isomer of JQ1 specifically inhibited IL-1β–induced activation and proliferation of RA-FLS in vitro. Transcriptomic and genomic profiling showed that JQ1 downregulated BET family members BRD2/BRD4, which are superenhancer genes, and altered chromatin occupancy of critical proinflammatory transcription factors. These results indicate that JQ1 has multiple effects on RA-FLS, and should stimulate further studies with BET inhibitors to explore their potential as therapeutic treatments for RA.
Perforin-Independent Granzyme B Signals
Traditionally, granzyme B (GrB) is thought to require perforin to enter a target cell. However, in this Top Read, Gapud et al. (p. 335) demonstrate that GrB can initiate intracellular signaling cascades in the absence of perforin. Cells incubated with recombinant GrB did not have increased cell death but did show substoichiometric levels of cleavage of multiple intracellular proteins. An enzymatically inactive mutant of GrB failed to induce cleavage fragments, suggesting GrB protease activity was required to cleave the intracellular proteins. GrB activated group II caspases and inhibitor of caspase-activated DNAse, indicating a role for the DNA damage response (DDR) in perforin-independent GrB signaling. DDR downstream phospho-protein signals, including PI3K-like kinases, were detected from cell lysates following GrB treatment. The activation of these kinases in turn resulted in phosphorylation of IRF-3 at S386, indicative of DNA damage-induced IRF-3 activation. Together, these data suggest that GrB, independent of perforin, can interface with innate immune responses through the DDR signaling pathway.
- Copyright © 2021 by The American Association of Immunologists, Inc.
