The monoterpene gamma-terpinene is a natural compound present in essential oils of a wide variety of plants, including the Eucalyptus genus, which has been reported to possess anti-inflammatory activity. The goal of this study was to evaluate the effect of gamma-terpinene on several in vivo experimental models of acute inflammation. Swiss mice were pretreated with gamma-terpinene and subjected to protocols of paw edema with different phlogistic agents such as carrageenan, prostaglandin-E₂, histamine, or bradykinin. The microvascular permeability was measured by intraperitoneal injection of acetic acid and measuring the amount of protein extravasation. Carrageenan-induced peritonitis was used to analyze the effect of gamma-terpinene on inflammatory cell migration and cytokine production. We also developed an acute lung injury protocol to define the anti-inflammatory effect of gamma-terpinene. Mice pretreated with gamma-terpinene displayed reduced paw edema induced by carrageenan from 1–24 h after challenge. A similar reduction was observed when gamma-terpinene was administered after stimulation with PGE₂, bradykinin, and histamine. Treatment with gamma-terpinene also inhibited fluid extravasation in the acetic acid model of microvascular permeability. In a carrageenan-induced peritonitis model, gamma-terpinene treatment reduced neutrophil migration as well as the production of interleukin-1β and tumor necrosis factor-α when compared to nontreated animals, and in the acute lung injury protocol, gamma-terpinene diminished the neutrophil migration into lung tissue independently of the total protein extravasation in the lung. These data demonstrate that, in different models of inflammation, treatment with gamma-terpinene alleviated inflammatory parameters such as edema and pro-inflammatory cytokine production, as well as cell migration into the inflamed site, and that this monoterpene has anti-inflammatory properties.

Severe forms of malaria are associated with systemic inflammation and host metabolism disorders; however, the interplay between these outcomes is poorly understood. Using a Plasmodium chabaudi model of malaria, we demonstrate that interferon (IFN) γ boosts glycolysis in splenic monocyte-derived dendritic cells (MODCs), leading to itaconate accumulation and disruption in the TCA cycle. Increased itaconate levels reduce mitochondrial functionality, which associates with organellar nucleic acid release and MODC restraint. We hypothesize that dysfunctional mitochondria release degraded DNA into the cytosol. Once mitochondrial DNA is sensitized, the activation of IRF3 and IRF7 promotes the expression of IFN-stimulated genes and checkpoint markers. Indeed, depletion of the STING-IRF3/IRF7 axis reduces PD-L1 expression, enabling activation of CD8+ T cells that control parasite proliferation. In summary, mitochondrial disruption caused by itaconate in MODCs leads to a suppressive effect in CD8+ T cells, which enhances parasitemia. We provide evidence that ACOD1 and itaconate are potential targets for adjunct antimalarial therapy.

Type 1 diabetes is associated with systemic low grade inflammation (LGI). We have previously shown that LGI in diabetic mice depends on systemic circulation of leukotriene (LTB₄) which potentiates thetoll-like/IL1β receptors response in macrophages. Impaired wound healing is an important co-morbidity in diabetes, and macrophages play a key role in this process. Here, we investigated the role of leukotrienes on monocytes and macrophages phenotype and in the impaired wound healing in diabetic mice. Type 1 diabetes was induced with streptozotocin in 129SvE wild-type (WT) and leukotrienes-deficient 5LO^−/−(5-lipoxygenaseknockout) mice. In diabetics, the systemic levels of LTB4, TNF-α, IL-6, IL-10, IL-12 and IFNγ were increased as well as the frequency of pro-inflammatory monocytes (CD11b⁺Ly6C^highLy6G⁻) compared to healthy mice. In diabetic 5LO^−/−mice, these parameters were similar to those in healthy mice. Resident peritoneal macrophages from diabetic WT mice showed a classically activated M1-like phenotype (highNos2,StatandIl12expression, and nitrite levels). Macrophages from diabetic 5LO^−/−mice presented alternatively activated M2-macrophages markers (highArg1andChi3l3expression and arginase activity) and when stimulated with IL4, enhanced phosphorylated-STAT6. Cutaneous wound healing in diabetic WT mice was impaired, which correlated with the decreased frequency of M2-macrophages (CD45⁺F4/80⁺CD206⁺) in the lesions. In diabetic 5LO^−/−mice, the frequency of M2-macrophages in the wound was similar to that in healthy mice, suggesting that the impaired healing of diabetic mice depends on 5LO products. The inhibition of leukotrienes or antagonism of its receptors could be a therapeutic alternative for diabetic patients with impaired healing.

Obesity is an increasingly costly and widespread epidemic, effecting 1 in 10 adults worldwide. It has been causally linked with both the metabolic syndrome and insulin resistance, both of which are associated with increased chronic inflammation. The exact mechanisms through which inflammation may contribute to both MetS and IR are numerous and their details are still largely unknown. Recently, micro-RNAs (miRNAs) have emerged as potential interventional targets due to their potential preventive roles in the pathogenesis of several diseases, including MetS and obesity. The purpose of this review paper is to discuss some of the known roles of miRNAs as mediators of inflammation-associated obesity and IR and how omega-3 polyunsaturated fatty acids may be used as a nutritional intervention for these disorders.

Mitochondria are perhaps best known as the “powerhouse of the cell” for their role in ATP production required for numerous cellular activities. Mitochondria have emerged as an important signaling organelle. Here, we first focus on signaling pathways mediated by mitochondria-nuclear communication that promote protein homeostasis (proteostasis). We examine the mitochondrial unfolded protein response (UPRmt) in C. elegans, which is regulated by a transcription factor harboring both a mitochondrial- and nuclear-targeting sequence, the integrated stress response in mammals, as well as the regulation of chromatin by mitochondrial metabolites. In the second section, we explore the role of mitochondria-to-nuclear communication in the regulation of innate immunity and inflammation. Perhaps related to their prokaryotic origin, mitochondria harbor molecules also found in viruses and bacteria. If these molecules accumulate in the cytosol, they elicit the same innate immune responses as viral or bacterial infection.