Thermal injury-induced immunosuppression in mice: the role of macrophage-derived reactive nitrogen intermediates

Schwacha, Martin G.; Somers, Scott D.

doi:10.1002/jlb.63.1.51

Cited by 74 publications

(96 citation statements)

References 60 publications

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“…Work by our laboratory and others has previously identified a suppressive role for the APC (i.e., macrophages and/or dendritic cells) after burn injury in experimental mouse models (2,21,36,37) and humans (10). In our studies, we did not distinguish whether the APCs responsible for injury-induced immune suppression were monocytes/macrophages vs dendritic cells, because we used a mixture of anti-F4/80 and anti-CD11c mAbs to isolate the cells.…”

Section: Discussionmentioning

confidence: 94%

Injury-Induced Suppression of Effector T Cell Immunity Requires CD1d-Positive APCs and CD1d-Restricted NKT Cells

Palmer

Tulley

Kovacs

et al. 2006

The Journal of Immunology

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Overwhelming infection remains the leading cause of death from serious burn injury despite recent advances in the care of burn patients and a better understanding of immune and inflammatory consequences of injury. In this study, we report a critical requirement for CD1d-restricted NKT cells and CD1d expression by APCs in the immune dysfunction that occurs early after burn injury. Using a well-established murine scald injury model with BALB/c and BALB/c CD1d knockout mice, we investigated whether peripheral T cell immunity was affected by the presence or absence of CD1d-restricted NKT cells in the early stages after injury. Using Ag-specific delayed-type hypersensitivity, T cell proliferation, and cytokine production as indices of immune responsiveness, we observed that both CD1d expression by APCs and CD1d-restricted NKT cells are required for immune suppression after injury. Via adoptive transfer of splenocytes from injured mice to uninjured recipients, we found injury-induced suppression of immunity to be Ag specific, long lasting, and critically dependent on cell surface expression of CD1d by APCs. Together, our results suggest that the defects in T cell responsiveness that occur subsequent to severe burn injury are not merely the result of global or passive suppression, but instead represent an active form of CD1d/NKT cell-dependent immunologic tolerance.

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Section: Discussionmentioning

confidence: 94%

Injury-Induced Suppression of Effector T Cell Immunity Requires CD1d-Positive APCs and CD1d-Restricted NKT Cells

Palmer

Tulley

Kovacs

et al. 2006

The Journal of Immunology

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“…Mice received a third-degree full-thickness scald burn as previously described [7,10,25]. Briefly, the mice were anesthetized by intraperitoneal injection of 65 mg/kg body weight pentobarbital sodium, and the entire dorsal surface was shaved.…”

Section: Thermal Injury Proceduresmentioning

confidence: 99%

“…The surviving mice were killed by methoxyflurane overdose at 7 days after injury, the time of maximal immunosuppression [10], and the spleens were removed aseptically. Splenocyte suspensions were prepared in complete media (RPMI 1640 containing 10% heat-inactivated fetal bovine serum, 50 µM ␤-mercaptoethanol, and 5 µg/mL gentamicin, GIBCO BRL, Grand Island, NY) as described elsewhere [10,25].…”

Section: Preparation Of Splenic Macrophagesmentioning

confidence: 99%

“…Previous studies assessing T lymphocyte function following thermal injury have primarily used T lymphocytes purified from the spleen [6,10] and peripheral circulation [1]. These cells are almost exclusively of the ␣␤ T cell receptor (TCR) lineage [11].…”

Section: Introductionmentioning

confidence: 99%

“…Macrophages are major producers of these inflammatory mediators and their productive capacity for them is markedly enhanced after thermal injury [7,9,10]. Thermal injury appears to prime macrophages to subsequent stimuli as evidenced by enhanced in vitro production of inflammatory mediators [22,23].…”

Section: Introductionmentioning

confidence: 99%

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Insights into the role of γδ T lymphocytes in the immunopathogenic response to thermal injury

Schwacha

Ayala

Chaudry

2000

Journal of Leukocyte Biology

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Studies have shown that cell-mediated immunity is markedly suppressed after thermal injury. T lymphocyte dysfunction and macrophage hyperactivity have been implicated as causative factors. Previous studies have primarily examined the effects of thermal injury on ␣␤ T lymphocytes; however, the role of ␥␦ T lymphocytes in the immune response after thermal injury is unclear. Therefore, wild-type mice and mice lacking the TCR ␦ gene (TCR ␦ ؊/؊ ) were subjected to a thirddegree scald burn and cell-mediated immune responses assessed at 7 days post-injury. TCR ␦ ؊/؊ mice had 75% mortality after burn injury compared with 25% mortality in the wild-type group. Plasma interluekin-6 (IL-6) levels were significantly elevated at 2, 4, and 18 h post-injury, whereas no difference was observed in tumor necrosis factor ␣ (TNF-␣) and prostaglandin E 2 (PGE 2 ) plasma levels. Plasma levels of these inflammatory mediators were similar in wild-type and TCR ␦ ؊/؊ mice post-injury. Splenic macrophage PGE 2 , IL-6, TNF-␣, and IL-10 production was significantly increased in wild-type mice at 7 days post-injury, whereas macrophages from injured TCR ␦ ؊/؊ mice had a significantly attenuated capacity to produce IL-6 and TNF-␣. In contrast, the increased release of PGE 2 and IL-10 by macrophages post-injury was not reduced in TCR ␦ ؊/؊ mice. These results implicate a dual role for ␥␦ T lymphocytes in the immunopathogenic response to burn injury: (1) they contribute to survival from the insult; and (2) they mediate the induction of a pro-inflammatory macrophage phenotype at 7 days post-injury. Thus, ␥␦ T lymphocytes, in part through the modulation of macrophage activity, appear to contribute to the immune dysfunction after thermal injury. J. Leukoc. Biol. 67: 644-650; 2000.

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Polysubstituted Pyrimidines as mPGES‐1 Inhibitors: Discovery of Potent Inhibitors of PGE₂ Production with Strong Anti‐inflammatory Effects in Carrageenan‐Induced Rat Paw Edema

et al. 2020

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We report an extensive structure‐activity relationship optimization of polysubstituted pyrimidines that led to the discovery of 5‐butyl‐4‐(4‐benzyloxyphenyl)‐6‐phenylpyrimidin‐2‐amine, and its difluorinated analogue. These compounds are sub‐micromolar inhibitors of PGE2 production (IC50 as low as 12 nM). In order to identify the molecular target of anti‐inflammatory pyrimidines, we performed extensive studies including enzymatic assays, homology modeling and docking. The difluorinated analogue simultaneously inhibits two key enzymes of the arachidonic acid cascade, namely mPGES‐1 and COX‐2, with mPGES‐1 inhibition being the principal mechanism of action. Other pyrimidines studied are potent mPGES‐1 inhibitors with no observed inhibition of COX‐1/2 enzymes. Moreover, the two most potent compounds proved to be significantly effective in vivo in a model of acute inflammation, suppressing carrageenan‐induced rat paw edema by 36 and 46 %. The promising results of this study warrant further preclinical evaluation of selected anti‐inflammatory candidates.

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Thermal injury-induced immunosuppression in mice: the role of macrophage-derived reactive nitrogen intermediates

Cited by 74 publications

References 60 publications

Injury-Induced Suppression of Effector T Cell Immunity Requires CD1d-Positive APCs and CD1d-Restricted NKT Cells

Injury-Induced Suppression of Effector T Cell Immunity Requires CD1d-Positive APCs and CD1d-Restricted NKT Cells

Insights into the role of γδ T lymphocytes in the immunopathogenic response to thermal injury

Polysubstituted Pyrimidines as mPGES‐1 Inhibitors: Discovery of Potent Inhibitors of PGE₂ Production with Strong Anti‐inflammatory Effects in Carrageenan‐Induced Rat Paw Edema

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Thermal injury-induced immunosuppression in mice: the role of macrophage-derived reactive nitrogen intermediates

Cited by 74 publications

References 60 publications

Injury-Induced Suppression of Effector T Cell Immunity Requires CD1d-Positive APCs and CD1d-Restricted NKT Cells

Injury-Induced Suppression of Effector T Cell Immunity Requires CD1d-Positive APCs and CD1d-Restricted NKT Cells

Insights into the role of γδ T lymphocytes in the immunopathogenic response to thermal injury

Polysubstituted Pyrimidines as mPGES‐1 Inhibitors: Discovery of Potent Inhibitors of PGE2 Production with Strong Anti‐inflammatory Effects in Carrageenan‐Induced Rat Paw Edema

Contact Info

Product

Resources

About

Polysubstituted Pyrimidines as mPGES‐1 Inhibitors: Discovery of Potent Inhibitors of PGE₂ Production with Strong Anti‐inflammatory Effects in Carrageenan‐Induced Rat Paw Edema