Arginase 1 is negatively regulated by β-catenin signaling in the lung

ABSTRACTWe previously demonstrated that mice lacking the Wnt co-receptor, Lrp5, had attenuated pulmonary fibrosis in the bleomycin model. We found that Arginase 1 (Arg1), an enzyme that converts L-arginine to urea and ornithine, was markedly elevated in Lrp5-/- lungs compared with wild-type mice after bleomycin injury. We show that this induction is not apparently due to the expression of Th2 cytokines, IL-4 and IL-13, but instead is due to Wnt/β-catenin signaling, which negatively regulates Arg1 expression in lung macrophages. Although Arg1 expression in macrophages has been used to define an alternatively activated phenotype, flow cytometry analysis of alveolar and interstitial macrophage sub-populations in Lrp5-/- lungs 14 days after bleomycin injury revealed no clear evidence of skewing from a classical to an alternatively activated phenotype. Upregulation of Arg1 expression and arginase activity might diminish lung arginine levels with consequent alterations in collagen or cytokine production. However, dietary supplementation of bleomycin-treated Lrp5-/- mice with the Arg1 substrate, L-arginine, failed to alter lung collagen content or cytokine levels 21 days after bleomycin injury. These findings demonstrate that Arg1 is negatively regulated by β-catenin signaling in macrophages, raising the possibility that Wnt signaling directs alterations in immune cell metabolism that may be relevant to lung repair after injury.

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DAP12 (KARAP) amplifies inflammation and increases mortality from endotoxemia and septic peritonitis

Journal of Experimental Medicine ◽

10.1084/jem.20050986 ◽

2005 ◽

Vol 202 (3) ◽

pp. 363-369 ◽

Cited By ~ 65

Author(s):

Isaiah R. Turnbull ◽

Jonathan E. McDunn ◽

Toshiyuki Takai ◽

R. Reid Townsend ◽

J. Perren Cobb ◽

...

Keyword(s):

Septic Shock ◽

Cytokine Production ◽

Ex Vivo ◽

Cecal Ligation ◽

Wild Type ◽

Macrophage Response ◽

Cytokine Levels ◽

Septic Peritonitis ◽

Microbial Products

DAP12 (KARAP) is a transmembrane signaling adaptor for a family of innate immunoreceptors that have been shown to activate granulocytes and monocytes/macrophages, amplifying production of inflammatory cytokines. Contrasting with these data, recent studies suggest that DAP12 signaling has an inhibitory role in the macrophage response to microbial products (Hamerman, J.A., N.K. Tchao, C.A. Lowell, and L.L. Lanier. 2005. Nat. Immunol. 6:579–586). To determine the in vivo role for DAP12 signaling in inflammation, we measured the response of wild-type (WT) and DAP12−/− mice to septic shock. We show that DAP12−/− mice have improved survival from both endotoxemia and cecal ligation and puncture–induced septic shock. As compared with WT mice, DAP12−/− mice have decreased plasma cytokine levels and a decreased acute phase response during sepsis, but no defect in the recruitment of cells or bacterial control. In cells isolated after sepsis and stimulated ex vivo, DAP12 signaling augments lipopolysaccharide-mediated cytokine production. These data demonstrate that, during sepsis, DAP12 signaling augments the response to microbial products, amplifying inflammation and contributing to mortality.

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Efferocytosis potentiates the expression of arachidonate 15-lipoxygenase (ALOX15) in alternatively activated human macrophages through LXR activation

Cell Death and Differentiation ◽

10.1038/s41418-020-00652-4 ◽

2020 ◽

Author(s):

Ryan G. Snodgrass ◽

Yvonne Benatzy ◽

Tobias Schmid ◽

Dmitry Namgaladze ◽

Malwina Mainka ◽

...

Keyword(s):

Gene Expression ◽

Tissue Repair ◽

Cell Function ◽

Immune Cell ◽

Inflammatory Responses ◽

Interleukin 1 ◽

Th2 Cytokines ◽

Alternatively Activated Macrophages ◽

Anti Inflammatory ◽

Alternatively Activated

Abstract Macrophages acquire anti-inflammatory and proresolving functions to facilitate resolution of inflammation and promote tissue repair. While alternatively activated macrophages (AAMs), also referred to as M2 macrophages, polarized by type 2 (Th2) cytokines IL-4 or IL-13 contribute to the suppression of inflammatory responses and play a pivotal role in wound healing, contemporaneous exposure to apoptotic cells (ACs) potentiates the expression of anti-inflammatory and tissue repair genes. Given that liver X receptors (LXRs), which coordinate sterol metabolism and immune cell function, play an essential role in the clearance of ACs, we investigated whether LXR activation following engulfment of ACs selectively potentiates the expression of Th2 cytokine-dependent genes in primary human AAMs. We show that AC uptake simultaneously upregulates LXR-dependent, but suppresses SREBP-2-dependent gene expression in macrophages, which are both prevented by inhibiting Niemann–Pick C1 (NPC1)-mediated sterol transport from lysosomes. Concurrently, macrophages accumulate sterol biosynthetic intermediates desmosterol, lathosterol, lanosterol, and dihydrolanosterol but not cholesterol-derived oxysterols. Using global transcriptome analysis, we identify anti-inflammatory and proresolving genes including interleukin-1 receptor antagonist (IL1RN) and arachidonate 15-lipoxygenase (ALOX15) whose expression are selectively potentiated in macrophages upon concomitant exposure to ACs or LXR agonist T0901317 (T09) and Th2 cytokines. We show priming macrophages via LXR activation enhances the cellular capacity to synthesize inflammation-suppressing specialized proresolving mediator (SPM) precursors 15-HETE and 17-HDHA as well as resolvin D5. Silencing LXRα and LXRβ in macrophages attenuates the potentiation of ALOX15 expression by concomitant stimulation of ACs or T09 and IL-13. Collectively, we identify a previously unrecognized mechanism of regulation whereby LXR integrates AC uptake to selectively shape Th2-dependent gene expression in AAMs.

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CD40 deficiency in mice exacerbates obesity-induced adipose tissue inflammation, hepatic steatosis, and insulin resistance

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00514.2012 ◽

2013 ◽

Vol 304 (9) ◽

pp. E951-E963 ◽

Cited By ~ 34

Author(s):

Chang-An Guo ◽

Sophia Kogan ◽

Shinya U. Amano ◽

Mengxi Wang ◽

Sezin Dagdeviren ◽

...

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Hepatic Steatosis ◽

Immune Cell ◽

Ex Vivo ◽

Liver Steatosis ◽

Epididymal Adipose Tissue ◽

Low Grade ◽

Wild Type ◽

Cytokine Levels

The pathophysiology of obesity and type 2 diabetes in rodents and humans is characterized by low-grade inflammation in adipose tissue and liver. The CD40 receptor and its ligand CD40L initiate immune cell signaling promoting inflammation, but conflicting data on CD40L-null mice confound its role in obesity-associated insulin resistance. Here, we demonstrate that CD40 receptor-deficient mice on a high-fat diet display the expected decrease in hepatic cytokine levels but paradoxically exhibit liver steatosis, insulin resistance, and glucose intolerance compared with their age-matched wild-type controls. Hyperinsulinemic-euglycemic clamp studies also demonstrated insulin resistance in glucose utilization by the CD40-null mice compared with wild-type mice. In contrast to liver, adipose tissue in CD40-deficient animals harbors elevated cytokine levels and infiltration of inflammatory cells, particularly macrophages and CD8+effector T cells. In addition, ex vivo explants of epididymal adipose tissue from CD40−/−mice display elevated basal and isoproterenol-stimulated lipolysis, suggesting a potential increase of lipid efflux from visceral fat to the liver. These findings reveal that 1) CD40-null mice represent an unusual model of hepatic steatosis with reduced hepatic inflammation, and 2) CD40 unexpectedly functions in adipose tissue to attenuate its inflammation in obesity, thereby protecting against hepatic steatosis.

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Azithromycin Alters Macrophage Phenotype and Pulmonary Compartmentalization during Lung Infection with Pseudomonas

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01424-09 ◽

2010 ◽

Vol 54 (6) ◽

pp. 2437-2447 ◽

Cited By ~ 52

Author(s):

David J. Feola ◽

Beth A. Garvy ◽

Theodore J. Cory ◽

Susan E. Birket ◽

Heather Hoy ◽

...

Keyword(s):

Macrophage Activation ◽

Immune Cell ◽

Inflammatory Diseases ◽

Pulmonary Inflammation ◽

Mannose Receptor ◽

Lung Parenchyma ◽

Macrophage Phenotype ◽

Arginase 1 ◽

Alternatively Activated

ABSTRACT Infection with mucoid strains of Pseudomonas aeruginosa in chronic inflammatory diseases of the airway is difficult to eradicate and can cause excessive inflammation. The roles of alternatively activated and regulatory subsets of macrophages in this pathophysiological process are not well characterized. We previously demonstrated that azithromycin induces an alternatively activated macrophage-like phenotype in vitro. In the present study, we tested whether azithromycin affects the macrophage activation status and migration in the lungs of P. aeruginosa-infected mice. C57BL/6 mice received daily doses of oral azithromycin and were infected intratracheally with a mucoid strain of P. aeruginosa. The properties of macrophage activation, immune cell infiltration, and markers of pulmonary inflammation in the lung interstitial and alveolar compartments were evaluated postinfection. Markers of alternative macrophage activation were induced by azithromycin treatment, including the surface expression of the mannose receptor, the upregulation of arginase 1, and a decrease in the production of proinflammatory cytokines. Additionally, azithromycin increased the number of CD11b+ monocytes and CD4+ T cells that infiltrated the alveolar compartment. A predominant subset of CD11b+ cells was Gr-1 positive (Gr-1+), indicative of a subset of cells that has been shown to be immunoregulatory. These differences corresponded to decreases in neutrophil influx into the lung parenchyma and alteration of the characteristics of peribronchiolar inflammation without any change in the clearance of the organism. These results suggest that the immunomodulatory effects of azithromycin are associated with the induction of alternative and regulatory macrophage activation characteristics and alteration of cellular compartmentalization during infection.

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Sex differences in resident immune cell phenotype underlie more efficient acute inflammatory responses in female mice

Blood ◽

10.1182/blood-2011-03-340281 ◽

2011 ◽

Vol 118 (22) ◽

pp. 5918-5927 ◽

Cited By ~ 129

Author(s):

Ramona S. Scotland ◽

Melanie J. Stables ◽

Shimona Madalli ◽

Peter Watson ◽

Derek W. Gilroy

Keyword(s):

Cytokine Production ◽

Immune Cell ◽

Inflammatory Responses ◽

Cell Phenotype ◽

Macrophage Phenotype ◽

Blood Leukocytes ◽

Bacterial Killing ◽

Female Resident ◽

Cytokine Levels ◽

Lymphocyte Populations

Abstract Females are protected against mortality arising from severe sepsis; however, the precise mechanisms that confer this survival advantage in females over males are unclear. Resident leukocytes in resting tissues have a significant influence on circulating cytokine levels and recruitment of blood leukocytes during acute inflammatory responses. Whether the phenotype of resident leukocytes is distinct in females is unknown. In the present study, we show that the numbers of leukocytes occupying the naive peritoneal and pleural cavities is higher in female than in male mice and rats, comprising more T and B lymphocytes and macrophages. The altered immune cell composition of the female peritoneum is controlled by elevated tissue chemokine expression. Female resident macrophages also exhibit greater TLR expression and enhanced phagocytosis and NADPH oxidase–mediated bacterial killing. However, macrophage-derived cytokine production is diminished by proportionally more resident immunomodulatory CD4+ T lymphocytes. Ovarian hormones regulate macrophage phenotype, function, and numbers, but have no significant impact on T-lymphocyte populations in females. We have identified a fundamental sex difference in phenotype of resident leukocytes. We propose that the distinct resident leukocyte population in females allows aggressive recognition and elimination of diverse infectious stimuli without recruitment of circulating neutrophils or excessive cytokine production.

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CCR5 deficiency decreases susceptibility to experimental cerebral malaria

Blood ◽

10.1182/blood-2002-05-1493 ◽

2003 ◽

Vol 101 (11) ◽

pp. 4253-4259 ◽

Cited By ~ 82

Author(s):

Elodie Belnoue ◽

Michèle Kayibanda ◽

Jean-Christophe Deschemin ◽

Mireille Viguier ◽

Matthias Mack ◽

...

Keyword(s):

T Cells ◽

Cerebral Malaria ◽

Cd8 T Cells ◽

Cytokine Production ◽

Wild Type ◽

Experimental Cerebral Malaria ◽

Pathologic Features ◽

Th1 Cytokine ◽

The Brain ◽

Deficient Mice

Abstract Infection of susceptible mouse strains with Plasmodium berghei ANKA (PbA) is a valuable experimental model of cerebral malaria (CM). Two major pathologic features of CM are the intravascular sequestration of infected erythrocytes and leukocytes inside brain microvessels. We have recently shown that only the CD8+ T-cell subset of these brain-sequestered leukocytes is critical for progression to CM. Chemokine receptor–5 (CCR5) is an important regulator of leukocyte trafficking in the brain in response to fungal and viral infection. Therefore, we investigated whether CCR5 plays a role in the pathogenesis of experimental CM. Approximately 70% to 85% of wild-type and CCR5+/- mice infected with PbA developed CM, whereas only about 20% of PbA-infected CCR5-deficient mice exhibited the characteristic neurologic signs of CM. The brains of wild-type mice with CM showed significant increases in CCR5+ leukocytes, particularly CCR5+ CD8+ T cells, as well as increases in T-helper 1 (Th1) cytokine production. The few PbA-infected CCR5-deficient mice that developed CM exhibited a similar increase in CD8+ T cells. Significant leukocyte accumulation in the brain and Th1 cytokine production did not occur in PbA-infected CCR5-deficient mice that did not develop CM. Moreover, experiments using bone marrow (BM)–chimeric mice showed that a reduced but significant proportion of deficient mice grafted with CCR5+ BM develop CM, indicating that CCR5 expression on a radiation-resistant brain cell population is necessary for CM to occur. Taken together, these results suggest that CCR5 is an important factor in the development of experimental CM.

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Antitumor Effects of PRIMA-1 and PRIMA-1Met (APR246) in Hematological Malignancies: Still a Mutant P53-Dependent Affair?

Cells ◽

10.3390/cells10010098 ◽

2021 ◽

Vol 10 (1) ◽

pp. 98

Author(s):

Paola Menichini ◽

Paola Monti ◽

Andrea Speciale ◽

Giovanna Cutrona ◽

Serena Matis ◽

...

Keyword(s):

Hematological Malignancies ◽

Cell Metabolism ◽

Therapy Response ◽

Tp53 Gene ◽

Suppressor Gene ◽

Lower Percentage ◽

Mutant P53 ◽

Wild Type ◽

Antitumor Effects ◽

Tp53 Tumor Suppressor Gene

Because of its role in the regulation of the cell cycle, DNA damage response, apoptosis, DNA repair, cell migration, autophagy, and cell metabolism, the TP53 tumor suppressor gene is a key player for cellular homeostasis. TP53 gene is mutated in more than 50% of human cancers, although its overall dysfunction may be even more frequent. TP53 mutations are detected in a lower percentage of hematological malignancies compared to solid tumors, but their frequency generally increases with disease progression, generating adverse effects such as resistance to chemotherapy. Due to the crucial role of P53 in therapy response, several molecules have been developed to re-establish the wild-type P53 function to mutant P53. PRIMA-1 and its methylated form PRIMA-1Met (also named APR246) are capable of restoring the wild-type conformation to mutant P53 and inducing apoptosis in cancer cells; however, they also possess mutant P53-independent properties. This review presents the activities of PRIMA-1 and PRIMA-1Met/APR246 and describes their potential use in hematological malignancies.

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Surfactant protein A reduces TLR4 and inflammatory cytokine mRNA levels in neonatal mouse ileum

Scientific Reports ◽

10.1038/s41598-021-82219-y ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Lidan Liu ◽

Chaim Z. Aron ◽

Cullen M. Grable ◽

Adrian Robles ◽

Xiangli Liu ◽

...

Keyword(s):

Proinflammatory Cytokine ◽

Inflammatory Cytokine ◽

Protein A ◽

Surfactant Protein ◽

Surfactant Protein A ◽

Mrna Levels ◽

Wild Type ◽

Cytokine Mrna ◽

Protein Levels ◽

Cytokine Levels

AbstractLevels of intestinal toll-like receptor 4 (TLR4) impact inflammation in the neonatal gastrointestinal tract. While surfactant protein A (SP-A) is known to regulate TLR4 in the lung, it also reduces intestinal damage, TLR4 and inflammation in an experimental model of necrotizing enterocolitis (NEC) in neonatal rats. We hypothesized that SP-A-deficient (SP-A−/−) mice have increased ileal TLR4 and inflammatory cytokine levels compared to wild type mice, impacting intestinal physiology. We found that ileal TLR4 and proinflammatory cytokine levels were significantly higher in infant SP-A−/− mice compared to wild type mice. Gavage of neonatal SP-A−/− mice with purified SP-A reduced ileal TLR4 protein levels. SP-A reduced expression of TLR4 and proinflammatory cytokines in normal human intestinal epithelial cells (FHs74int), suggesting a direct effect. However, incubation of gastrointestinal cell lines with proteasome inhibitors did not abrogate the effect of SP-A on TLR4 protein levels, suggesting that proteasomal degradation is not involved. In a mouse model of experimental NEC, SP-A−/− mice were more susceptible to intestinal stress resembling NEC, while gavage with SP-A significantly decreased ileal damage, TLR4 and proinflammatory cytokine mRNA levels. Our data suggests that SP-A has an extrapulmonary role in the intestinal health of neonatal mice by modulating TLR4 and proinflammatory cytokines mRNA expression in intestinal epithelium.

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Role and Regulation of Adipokines during Zymosan-Induced Peritoneal Inflammation in Mice

Endocrinology ◽

10.1210/en.2008-0327 ◽

2008 ◽

Vol 149 (8) ◽

pp. 4080-4085 ◽

Cited By ~ 20

Author(s):

Maria Pini ◽

Melissa E. Gove ◽

Joseph A. Sennello ◽

Jantine W. P. M. van Baal ◽

Lawrence Chan ◽

...

Keyword(s):

Inflammatory Infiltrate ◽

Peritoneal Lavage ◽

Lavage Fluid ◽

Wild Type ◽

Cellular Infiltrate ◽

Peritoneal Lavage Fluid ◽

Peritoneal Inflammation ◽

Leptin Deficiency ◽

Cytokine Levels

Adipokines, cytokines mainly produced by adipocytes, are active participants in the regulation of inflammation. Administration of zymosan (ZY) was used to investigate the regulation and role of adipokines during peritonitis in mice. Injection of ZY led to a significant increase in leptin levels in both serum and peritoneal lavage fluid, whereas a differential trend in local vs. systemic levels was observed for both resistin and adiponectin. The role of leptin in ZY-induced peritonitis was investigated using leptin-deficient ob/ob mice, with and without reconstitution with exogenous leptin. Leptin deficiency was associated with delayed resolution of peritoneal inflammation induced by ZY, because ob/ob mice had a more pronounced cellular infiltrate in the peritoneum as well as higher and prolonged local and systemic levels of IL-6, TNFα, IL-10, and chemokine (C-X-C motif) ligand 2 compared with wild-type mice. Reconstitution with exogenous leptin exacerbated the inflammatory infiltrate and systemic IL-6 levels in ob/ob mice while inhibiting production of TNFα, IL-10, and chemokine (C-X-C motif) ligand 2. In contrast with the important role of leptin in regulating each aspect of ZY-induced peritonitis, adiponectin deficiency was associated only with a decreased inflammatory infiltrate, without affecting cytokine levels. These findings point to a complex role for adipokines in ZY-induced peritonitis and further emphasize the interplay between obesity and inflammation.

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Retinal microglia polarization in diabetic retinopathy

Visual Neuroscience ◽

10.1017/s0952523821000031 ◽

2021 ◽

Vol 38 ◽

Author(s):

Xin Li ◽

Zi-Wei Yu ◽

Hui-Yao Li ◽

Yue Yuan ◽

Xin-Yuan Gao ◽

...

Keyword(s):

Central Nervous System ◽

Diabetic Retinopathy ◽

Cytokine Production ◽

Immune Cell ◽

Microvascular Disease ◽

Retinal Diseases ◽

Microglia Polarization ◽

Retinal Microglia ◽

The Central Nervous System ◽

Retinal Neurodegeneration

Abstract Microglia, the main immune cell of the central nervous system (CNS), categorized into M1-like phenotype and M2-like phenotype, play important roles in phagocytosis, cell migration, antigen presentation, and cytokine production. As a part of CNS, retinal microglial cells (RMC) play an important role in retinal diseases. Diabetic retinopathy (DR) is one of the most common complications of diabetes. Recent studies have demonstrated that DR is not only a microvascular disease but also retinal neurodegeneration. RMC was regarded as a central role in neurodegeneration and neuroinflammation. Therefore, in this review, we will discuss RMC polarization and its possible regulatory factors in early DR, which will provide new targets and insights for early intervention of DR.

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