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Severe defects in human IFNγ immunity predispose individuals to both Bacillus Calmetteu2013Guérin disease and tuberculosis, whereas milder defects predispose only to tuberculosis1. Here we report two adults with recurrent pulmonary tuberculosis who are homozygous for a private loss-of-function TNF variant. Neither has any other clinical phenotype and both mount normal clinical and biological inflammatory responses. Their leukocytes, including monocytes and monocyte-derived macrophages (MDMs) do not produce TNF, even after stimulation with IFNγ. Blood leukocyte subset development is normal in these patients. However, an impairment in the respiratory burst was observed in granulocyteu2013macrophage colony-stimulating factor (GM-CSF)-matured MDMs and alveolar macrophage-like (AML) cells2 from both patients with TNF deficiency, TNF- or TNFR1-deficient induced pluripotent stem (iPS)-cell-derived GM-CSF-matured macrophages, and healthy control MDMs and AML cells differentiated with TNF blockers in vitro, and in lung macrophages treated with TNF blockers ex vivo. The stimulation of TNF-deficient iPS-cell-derived macrophages with TNF rescued the respiratory burst. These findings contrast with those for patients with inherited complete deficiency of the respiratory burst across all phagocytes, who are prone to multiple infections, including both Bacillus Calmetteu2013Guérin disease and tuberculosis3. Human TNF is required for respiratory-burst-dependent immunity to Mycobacterium tuberculosis in macrophages but is surprisingly redundant otherwise, including for inflammation and immunity to weakly virulent mycobacteria and many other infectious agents.

Hemophagocytic lymphohistocytosis (HLH) is characterized by fulminant cytokine storm leading to multiple organ dysfunction and high mortality. HLH is classified into familial (fHLH) and into secondary (sHLH). fHLH is rare and it is due to mutations of genes encoding for perforin or excretory granules of natural killer (NK) cells of CD8-lymphocytes. sHLH is also known as macrophage activation syndrome (MAS). Macrophage activation syndrome (MAS) in adults is poorly studied. Main features are fever, hepatosplenomegaly, hepatobiliary dysfunction (HBD), coagulopathy, cytopenia of two to three cell lineages, increased triglycerides and hemophagocytosis in the bone marrow. sHLH/MAS complicates hematologic malignancies, autoimmune disorders and infections mainly of viral origin. Pathogenesis is poorly understood and it is associated with increased activation of macrophages and NK cells. An autocrine loop of interleukin (IL)-1β over-secretion leads to cytokine storm of IL-6, IL-18, ferritin, and interferon-gamma; soluble CD163 is highly increased from macrophages. The true incidence of sHLH/MAS among patients with sepsis has only been studied in the cohort of the Hellenic Sepsis Study Group. Patients meeting the Sepsis-3 criteria and who had positive HSscore or co-presence of HBD and disseminated intravascular coagulation (DIC) were classified as patients with macrophage activation-like syndrome (MALS). The frequency of MALS ranged between 3 and 4% and it was an independent entity associated with early mortality after 10 days. Ferritin was proposed as a diagnostic and surrogate biomarker. Concentrations >4,420 ng/ml were associated with diagnosis of MALS with 97.1% specificity and 98% negative predictive value. Increased ferritin was also associated with increased IL-6, IL-18, IFNγ, and sCD163 and by decreased IL-10/TNFα ratio. A drop of ferritin by 15% the first 48 h was a surrogate finding of favorable outcome. There are 10 on-going trials in adults with sHLH; two for the development of biomarkers and eight for management. Only one of them is focusing in sepsis. The acronym of the trial is PROVIDE (ClinicalTrials.gov NCT03332225) and it is a double-blind randomized clinical trial aiming to deliver to patients with septic shock treatment targeting their precise immune state. Patients diagnosed with MALS are receiving randomized treatment with placebo or the IL-1β blocker anakinra.

[This corrects the article DOI: 10.1371/journal.pone.0306659.].

Plastic polarization of macrophage is involved in tumorigenesis. M1‐polarized macrophage mediates rapid inflammation, entity clearance and may also cause inflammation‐induced mutagenesis. M2‐polarized macrophage inhibits rapid inflammation but can promote tumour aggravation. ω‐3 long‐chain polyunsaturated fatty acid (PUFA)‐derived metabolites show a strong anti‐inflammatory effect because they can skew macrophage polarization from M1 to M2. However, their role in tumour promotive M2 macrophage is still unknown. Resolvin D1 and D2 (RvD1 and RvD2) are docosahexaenoic acid (DHA)‐derived docosanoids converted by 15‐lipoxygenase then 5‐lipoxygenase successively. We found that although dietary DHA can inhibit prostate cancer in vivo, neither DHA (10 μmol/L) nor RvD (100 nmol/L) can directly inhibit the proliferation of prostate cancer cells in vitro. Unexpectedly, in a cancer cell‐macrophage co‐culture system, both DHA and RvD significantly inhibited cancer cell proliferation. RvD1 and RvD2 inhibited tumour‐associated macrophage (TAM or M2d) polarization. Meanwhile, RvD1 and RvD2 also exhibited anti‐inflammatory effects by inhibiting LPS‐interferon (IFN)‐γ‐induced M1 polarization as well as promoting interleukin‐4 (IL‐4)‐mediated M2a polarization. These differential polarization processes were mediated, at least in part, by protein kinase A. These results suggest that regulation of macrophage polarization using RvDs may be a potential therapeutic approach in the management of prostate cancer.

[This corrects the article DOI: 10.1371/journal.pone.0181014.].[This corrects the article DOI: 10.1371/journal.pone.0181014.].

In patients with autoimmune pulmonary alveolar proteinosis, the use of inhaled recombinant granulocyte–macrophage colony-stimulating factor resulted in a significantly better alveolar–arterial oxygen gradient at 25 weeks than the use of placebo. The beneficial effect was not observed in smokers.

[This corrects the article DOI: 10.1371/journal.pone.0251578.].[This corrects the article DOI: 10.1371/journal.pone.0251578.].

Macrophages are innate immune cells that play key roles during both homeostasis and disease. Depending on the microenvironmental cues sensed in different tissues, macrophages are known to acquire specific phenotypes and exhibit unique features that, ultimately, orchestrate tissue homeostasis, defense, and repair. Within the tumor microenvironment, macrophages are referred to as tumor‐associated macrophages (TAMs) and constitute a heterogeneous population. Like their tissue resident counterpart, TAMs are plastic and can switch function and phenotype according to the niche‐derived stimuli sensed. While changes in TAM phenotype are known to be accompanied by adaptive alterations in their cell metabolism, it is reported that metabolic reprogramming of macrophages can dictate their activation state and function. In line with these observations, recent research efforts have been focused on defining the metabolic traits of TAM subsets in different tumor malignancies and understanding their role in cancer progression and metastasis formation. This knowledge will pave the way to novel therapeutic strategies tailored to cancer subtype‐specific metabolic landscapes. This review outlines the metabolic characteristics of distinct TAM subsets and their implications in tumorigenesis across multiple cancer types. Tumor‐associated macrophages (TAMs) constitute up to 50% of the tumor mass, representing a heterogeneous population of tissue‐resident and monocyte‐derived macrophages. TAM phenotype not only involves alterations in cell metabolism but also metabolic reprogramming that can dictate their activation state and function. This review elucidates the diverse roles and metabolic traits of distinct TAM subsets in pancreatic, breast, lung and ovarian malignancies.