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No abstract is provided for this article.

No abstract is provided for this article.

A New Linc in Innate Immunity Long noncoding RNAs (lncRNAs) have recently emerged as important regulators of gene expression in a wide variety of biological processes, although specific roles for these molecules in the immune system have not been described. Carpenter et al. (p. 789 , published online 1 August) now define the function of one such lncRNA in the immune system, lincRNA-Cox2. Whole-transcriptome profiling revealed that lincRNA-Cox2 was induced in mouse macrophages in response to activation of Toll-like receptors—molecules that detect microbes and alert the immune system to respond. LincRNA-Cox2 both positively and negatively regulated the expression of distinct groups of inflammatory genes. Negative regulation of gene expression was mediated by lincRNA-Cox interaction with heterogeneous nuclear ribonucleoprotein A/B and A2/B1.

Control of mitogen-activated protein kinase (MAPK) cascades is central to regulation of many cellular responses. We describe here human tribbles homologues (Htrbs) that control MAPK activity. MAPK kinases interact with Trbs and regulate their steady state levels. Further, Trbs selectively regulate the activation of extracellular signal-regulated kinases, c-Jun NH2-terminal kinases, and p38 MAPK with different relative levels of activity for the three classes of MAPK observed depending on the level of Trb expression. These results suggest that Trbs control both the extent and the specificity of MAPK kinase activation of MAPK.

TLR4 recognition of LPS triggers signalosome assembly among TLR4, sorting (e.g. MyD88‐adapter‐like, Mal) and signaling (e.g. MyD88) adapters and kinases, resulting in activation of transcription factors and production of inflammatory mediators. Here we examined whether Mal tyrosine phosphorylation regulates Mal‐TLR4 interactions and signaling. In contrast to wild‐type (WT) Mal, overexpression of tyrosine‐deficient Mal variants with mutated Y86, Y106, and Y159 tyrosine residues impaired Mal tyrosine phosphorylation, interactions with Bruton's tyrosine kinase (Btk), phosphorylation of p38, and NF‐κB activation. LPS triggered tyrosine phosphorylation of endogenous Mal and initiated Mal‐Btk interactions in 293/TLR4/MD‐2 cells and human monocytes that were suppressed in endotoxin‐tolerant cells. Compared to WT‐Mal, Y86A‐ and Y159A‐ Mal variants exhibited higher interactions with TLR4 and MyD88, while associations with IRAK‐2 and TRAF‐6 were not affected. Overexpression of Y86A, Y159A and Y106A Mal in 293/TLR4/MD‐2 cells exerted dominant‐negative effects on TLR4‐inducible p38 phosphorylation and NF‐κB reporter activation. In contrast, tyrosine‐deficient Mal species did not affect NF‐κB activation when signaling was initiated at the post‐receptor level by overexpression of MyD88, IRAK‐2 or TRAF‐6. Thus, tyrosine phosphorylation of Mal is required for TLR signaling, regulates Mal interactions with TLR4 and receptor signaling, and is inhibited in endotoxin tolerance. This work was supported by NIH grant AI‐059524 (to A.E.M.)

PGs are important proinflammatory lipid mediators, the significance of which is highlighted by the widespread and efficacious use of nonsteroidal anti-inflammatory drugs in the treatment of inflammation. 4-Octyl itaconate (4-OI), a derivative of the Krebs cycle–derived metabolite itaconate, has recently garnered much interest as an anti-inflammatory agent. In this article, we show that 4-OI limits PG production in murine macrophages stimulated with the TLR1/2 ligand Pam3CSK4. This decrease in PG secretion is due to a robust suppression of cyclooxygenase 2 (COX2) expression by 4-OI, with both mRNA and protein levels decreased. Dimethyl fumarate, a fumarate derivative used in the treatment of multiple sclerosis, with properties similar to itaconate, replicated the phenotype observed with 4-OI. We also demonstrate that the decrease in COX2 expression and inhibition of downstream PG production occurs in an NRF2-independent manner. Our findings provide a new insight into the potential of 4-OI as an anti-inflammatory agent and also identifies a novel anti-inflammatory function of dimethyl fumarate.

Macrophages are a highly adaptive population of innate immune cells. Polarization with IFNγ and LPS into the ‘classically activated’ M1 macrophage enhances pro-inflammatory and microbicidal responses, important for eradicating bacteria such as Mycobacterium tuberculosis . By contrast, ‘alternatively activated’ M2 macrophages, polarized with IL-4, oppose bactericidal mechanisms and allow mycobacterial growth. These activation states are accompanied by distinct metabolic profiles, where M1 macrophages favor near exclusive use of glycolysis, whereas M2 macrophages up-regulate oxidative phosphorylation (OXPHOS). Here, we demonstrate that activation with IL-4 and IL-13 counterintuitively induces protective innate memory against mycobacterial challenge. In human and murine models, prior activation with IL-4/13 enhances pro-inflammatory cytokine secretion in response to a secondary stimulation with mycobacterial ligands. In our murine model, enhanced killing capacity is also demonstrated. Despite this switch in phenotype, IL-4/13 trained murine macrophages do not demonstrate M1-typical metabolism, instead retaining heightened use of OXPHOS. Moreover, inhibition of OXPHOS with oligomycin, 2-deoxy glucose or BPTES all impeded heightened pro-inflammatory cytokine responses from IL-4/13 trained macrophages. Lastly, this work identifies that IL-10 attenuates protective IL-4/13 training, impeding pro-inflammatory and bactericidal mechanisms. In summary, this work provides new and unexpected insight into alternative macrophage activation states in the context of mycobacterial infection.

The past century has witnessed major advances in the control of many infectious diseases, yet outbreaks and epidemics caused by (re-) emerging RNA viruses continue to pose a global threat to human health. As illustrated by the global COVID19 pandemic, high healthcare costs, economic disruption and loss of productivity reinforce the unmet medical need to develop new antiviral strategies to combat not only the current pandemic but also future viral outbreaks. Pivotal for effective anti-viral defense is the innate immune system, a first line host response that senses and responds to virus infection. While molecular details of the innate immune response are well characterized, this research field is now being revolutionized with the recognition that cell metabolism has a major impact on the antiviral and inflammatory responses to virus infections. A detailed understanding of the role of metabolic regulation with respect to antiviral and inflammatory responses, together with knowledge of the strategies used by viruses to exploit immunometabolic pathways, will ultimately change our understanding and treatment of pathogenic viral diseases. INITIATE is a Marie Sklodowska-Curie Actions Innovative Training Network (MSCA-ITN), with the goal to train 15 early stage PhD researchers (ESRs) to become experts in antiviral immunometabolism (https://initiate-itn.eu/). To this end, INITIATE brings together a highly complementary international team of academic and corporate leaders from 7 European countries, with outstanding track records in the historically distinct research fields of virology, immunology and metabolism. The ESRs of INITIATE are trained in these interdisciplinary research fields through individual investigator-driven research projects, specialized scientific training events, workshops on academia-industry interactions, outreach & communication. INITIATE will deliver a new generation of creative and entrepreneurial researchers who will be able to face the inevitable future challenges in combating viral diseases.

The NLRP3 inflammasome is a cytosolic complex sensing phagocytosed material and various damage associated molecular patterns, triggering production of the proinflammatory cytokines IL-1β and IL-18, promoting pyroptosis. Here, we characterise Glutathione transferase omega 1-1 (GSTO1-1), a constitutive deglutathionylating enzyme, as a novel NLRP3 inflammasome regulator. Using a small molecule inhibitor of GSTO1-1 termed C1-27, endogenous GSTO1-1 knockdown and GSTO1-1-/- mice, we report that GSTO1-1 is involved in NLRP3 inflammasome activation. Mechanistically, GSTO1-1 deglutathionylates cysteine 253 in NIMA related kinase 7 (NEK7) to promote NLRP3 activation. GSTO1-1 is therefore identified as an NLRP3 inflammasome regulator, which has potential as a drug target to limit NLRP3-mediated inflammation.