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Newborns’ susceptibility to infection is mainly attributed to decreased neutrophil bone marrow reserves and peripheral blood neutropenia. However, the regulation of neonatal neutrophil kinetics in sepsis remains poorly understood. We demonstrate herein that the developmental endothelial locus (DEL-1) is elevated in early life and is integral to a protective host response in neonates, by supporting emergency granulopoiesis. DEL-1-deficient neonate mouse pups subjected to sepsis displayed diminished bone marrow numbers of neutrophils and granulocyte-macrophage progenitors, leading to neutropenia, exaggerated bacteremia, and increased mortality; defects that were rescued by DEL-1 administration. Contrary to adult mice, DEL-1 was not downregulated upon neonatal sepsis. The sustained production of DEL-1 under newborn sepsis was attributed to a high IL-10/IL-17A ratio, as we IL-10 upregulated DEL-1. The expression of DEL-1 and its effect in emergency granulopoiesis in neonates was diminished by anti-IL-10-Receptor blockage. Consistent with the mouse findings, DEL-1 and neutrophil numbers were higher in septic human adult and neonate patients with high IL-10/IL-17A ratio. Furthermore, septic patients with high DEL-1 exhibited lower mortality rates compared to patients with low DEL-1. These findings highlight the role of a hitherto unappreciated IL-10–DEL-1 axis in supporting emergency granulopoiesis, preventing neutropenia and promoting sepsis survival in early life.

Dehydroepiandrosterone (DHEA) is the most abundant circulating steroid hormone in humans, produced by the adrenals, the gonads and the brain. DHEA was previously shown to bind to the nerve growth factor receptor, tropomyosin-related kinase A (TrkA), and to thereby exert neuroprotective effects. Here we show that DHEA reduces microglia-mediated inflammation in an acute lipopolysaccharide-induced neuro-inflammation model in mice and in cultured microglia in vitro. DHEA regulates microglial inflammatory responses through phosphorylation of TrkA and subsequent activation of a pathway involving Akt1/Akt2 and cAMP response element-binding protein. The latter induces the expression of the histone 3 lysine 27 (H3K27) demethylase Jumonji d3 (Jmjd3), which thereby controls the expression of inflammation-related genes and microglial polarization. Together, our data indicate that DHEA-activated TrkA signaling is a potent regulator of microglia-mediated inflammation in a Jmjd3-dependent manner, thereby providing the platform for potential future therapeutic interventions in neuro-inflammatory pathologies.

Macrophages become activated initiating innate immune responses. Depending on the signals, macrophages obtain an array of activation phenotypes, described by the broad terms of M1 or M2 phenotype. The PI3K/Akt/mTOR pathway mediates signals from multiple receptors including insulin receptors, pathogen-associated molecular pattern receptors, cytokine receptors, adipokine receptors, and hormones. As a result, the Akt pathway converges inflammatory and metabolic signals to regulate macrophage responses modulating their activation phenotype. Akt is a family of three serine-threonine kinases, Akt1, Akt2, and Akt3. Generation of mice lacking individual Akt, PI3K, or mTOR isoforms and utilization of RNA interference technology have revealed that Akt signaling pathway components have distinct and isoform-specific roles in macrophage biology and inflammatory disease regulation, by controlling inflammatory cytokines, miRNAs, and functions including phagocytosis, autophagy, and cell metabolism. Herein, we review the current knowledge on the role of the Akt signaling pathway in macrophages, focusing on M1/M2 polarization and highlighting Akt isoform–specific functions.

// Ahmed A. Al-Qahtani 1,2 , Konstantina Lyroni 3 , Marina Aznaourova 3 , Melpomeni Tseliou 4 , Mashael R. Al-Anazi 1 , Mohammed N. Al-Ahdal 1,2 , Saad Alkahtani 5 , George Sourvinos 4,* and Christos Tsatsanis 3,* 1 Department of Infection and Immunity, Research Center, King Faisal Specialist Hospital and Research Center, Saudi Arabia 2 Department of Microbiology and Immunology, School of Medicine, Alfaisal University, Riyadh, Saudi Arabia 3 Laboratory of Clinical Chemistry, Medical School, University of Crete, Heraklion, Greece 4 Laboratory of Virology, Medical School, University of Crete, Heraklion, Greece 5 Zoology Department, College of Science, King Saud University, Riyadh, Saudi Arabia * These authors have contributed equally to this work Correspondence to: Christos Tsatsanis, email: // George Sourvinos, email: // Keywords : MERS CoV, macrophages, DPP4, IRAK-M, cytokines, Immunology and Microbiology Section, Immune response, Immunity Received : July 22, 2016 Accepted : January 10, 2017 Published : January 19, 2017 Abstract Middle East Respiratory Syndrome Corona Virus (MERS-CoV) is transmitted via the respiratory tract and causes severe Acute Respiratory Distress Syndrome by infecting lung epithelial cells and macrophages. Macrophages can readily recognize the virus and eliminate it. MERS-CoV infects cells via its Spike (S) glycoprotein that binds on Dipeptidyl-Peptidase 4 (DPP4) receptor present on macrophages. Whether this Spike/DPP4 association affects macrophage responses remains unknown. Herein we demonstrated that infection of macrophages with lentiviral particles pseudotyped with MERS-CoV S glycoprotein results in suppression of macrophage responses since it reduced the capacity of macrophages to produce TNFα and IL-6 in naive and LPS-activated THP-1 macrophages and augmented LPS-induced production of the immunosuppressive cytokine IL-10. MERS-CoV S glycoprotein induced the expression of the negative regulator of TLR signaling IRAK-M as well as of the transcriptional repressor PPARγ. Inhibition of DPP4 by its inhibitor sitagliptin or siRNA abrogated the effects of MERS-CoV S glycoprotein on IRAK-M, PPARγ and IL-10, confirming that its immunosuppressive effects were mediated by DPP4 receptor. The effect was observed both in THP-1 macrophages and human primary peripheral blood monocytes. These findings support a DPP4-mediated suppressive action of MERS-CoV in macrophages and suggest a potential target for effective elimination of its pathogenicity.

The infiltration and subsequent in situ subtype specification of monocytes to effector/inflammatory and repair macrophages is indispensable for tissue repair upon acute sterile injury. However, the chromatin-level mediators and regulatory events controlling this highly dynamic macrophage phenotype switch are not known. In this study, we used a murine acute muscle injury model to assess global chromatin accessibility and gene expression dynamics in infiltrating macrophages during sterile physiological inflammation and tissue regeneration. We identified a heme-binding transcriptional repressor, BACH1, as a novel regulator of this process. Bach1 knockout mice displayed impaired muscle regeneration, altered dynamics of the macrophage phenotype transition, and transcriptional deregulation of key inflammatory and repair-related genes. We also found that BACH1 directly binds to and regulates distal regulatory elements of these genes, suggesting a novel role for BACH1 in controlling a broad spectrum of the repair response genes in macrophages upon injury. Inactivation of heme oxygenase-1 (Hmox1), one of the most stringently deregulated genes in the Bach1 knockout in macrophages, impairs muscle regeneration by changing the dynamics of the macrophage phenotype switch. Collectively, our data suggest the existence of a heme–BACH1­–HMOX1 regulatory axis, that controls the phenotype and function of the infiltrating myeloid cells upon tissue damage, shaping the overall tissue repair kinetics.

Skeletal muscle regeneration following injury is a complex process that involves inflammatory components. Macrophage infiltration to damaged tissues upon injuries and their in-situ differentiation ...

Chagas disease is caused by infection with the protozoan Trypanosoma cruzi (T. cruzi) and is an important cause of severe inflammatory heart disease. However, the mechanisms driving Chagas disease cardiomyopathy have not been completely elucidated. Here, we show that the canonical PI3Kγ pathway is upregulated in both human chagasic hearts and hearts of acutely infected mice. PI3Kγ-deficient mice and mutant mice carrying catalytically inactive PI3Kγ are more susceptible to T. cruzi infection. The canonical PI3Kγ signaling in myeloid cells is essential to restrict T. cruzi heart parasitism and ultimately to avoid myocarditis, heart damage, and death of mice. Furthermore, high PIK3CG expression correlates with low parasitism in human Chagas’ hearts. In conclusion, these results indicate an essential role of the canonical PI3Kγ signaling pathway in the control of T. cruzi infection, providing further insight into the molecular mechanisms involved in the pathophysiology of chagasic heart disease., Trypanosoma cruzi infection causes Chagas disease, but mechanisms underlying pathogenesis are unclear. Here, Silva et al. show that canonical PI3Kγ signaling in myeloid cells restricts T. cruzi infection in mice and that high PIK3CG expression correlates with low parasite levels in human Chagas’ hearts.

Obesity and insulin resistance influences metabolic processes, but whether it affects macrophage metabolism is not known. In this study, we demonstrate that chronic exposure of macrophages to insulin either in culture or in vivo in diet-induced, glucose-intolerant mice rendered them resistant to insulin signals marked by failure to induce Akt2 phosphorylation. Similarly, macrophages lacking Akt2 or IGF1 receptor were also resistant to insulin signals. Insulin-resistant macrophages had increased basal mTORC1 activity, possessed an M2-like phenotype, and reduced LPS responses. Moreover, they exhibited increased glycolysis and increased expression of key glycolytic enzymes. Inhibition of mTORC1 reversed the M2-like phenotype and suppressed glycolysis in insulin-resistant macrophages. In the context of polymicrobial sepsis, mice harboring insulin-resistant macrophages exhibited reduced sepsis-induced lung injury. Thus, macrophages obtain resistance to insulin characterized by increased glycolysis and a unique M2-like phenotype, termed M-insulin resistant, which accounts for obesity-related changes in macrophage responses and a state of trained immunity.

Adipose tissue is not only involved in energy storage but also functions as an immuno-regulatory organ that participates in the establishment of obesity-related chronic low-grade inflammation. In this work we questioned whether adipocytes themselves could acquire a pro- or anti- inflammatory phenotype and determine potential signaling molecules affecting this process. The results showed that MEF-derived adipocytes were activated by LPS or IL-4. Si-RNA library screening allowed the identification of signaling molecules regulating iNOS and Arg1 expression and showed that PPARγ STAT3 and Akt2 were central regulators. In vivo, we found adipocytes from Akt2-/- mice or from HFD-induced obese mice had increased expression of iNOS and Arg1 and the pro-inflammatory cytokine osteopontin (OPN). Surprisingly, genetic deletion of OPN resulted in increased responsiveness of adipocytes to LPS as determined by elevated expression of iNOS and NO production. Despite the increased NO production Arg1 and IL-10 were also higher in OPN-/- adipocytes suggesting that OPN affects additional signaling events that suppress adipocyte activation. Further analysis determined the signaling components affected by OPN that regulate inflammatory factors in adipocytes. Our findings suggest that adipocytes obtain pro- or anti-inflammatory properties, which are affected by obesity. OPN partly regulates the anti-inflammatory properties of adipocytes by initiating anti- inflammatory cascades.