Increased monocyte TNF-α message stability contributes to trauma patients' increased TNF production

Furse, Robert K.; Kodys, Karen; Zhu, Di; Miller-Graziano, Carol L.

doi:10.1002/jlb.62.4.524

Cited by 12 publications

(14 citation statements)

References 50 publications

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“…In conclusion, we show that systemic administration of ARA290 is highly effective in reducing burn wound expansion by preventing microvascular thrombosis and progressive necrosis, which correlated with a decrease in TNF-α secretion levels of innate immune cells, including several markers of related proinflammatory pathways in the wounds (37,38). The decrease in burn depth and area would likely reduce the necessity for extensive surgical debridement as well as secondary wound closure by means of skin grafting.…”

Section: Discussionmentioning

confidence: 63%

Alternative erythropoietin-mediated signaling prevents secondary microvascular thrombosis and inflammation within cutaneous burns

Bohr

Patel

Shen

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Alternate erythropoietin (EPO)–mediated signaling via the heteromeric receptor composed of the EPO receptor and the β-common receptor (CD131) exerts the tissue-protective actions of EPO in various types of injuries. Herein we investigated the effects of the EPO derivative helix beta surface peptide (synonym: ARA290), which specifically triggers alternate EPO-mediated signaling, but does not bind the erythropoietic EPO receptor homodimer, on the progression of secondary tissue damage following cutaneous burns. For this purpose, a deep partial thickness cutaneous burn injury was applied on the back of mice, followed by systemic administration of vehicle or ARA290 at 1, 12, and 24 h postburn. With vehicle-only treatment, wounds exhibited secondary microvascular thrombosis within 24 h postburn, and subsequent necrosis of the surrounding tissue, thus converting to a full-thickness injury within 48 h. On the other hand, when ARA290 was systemically administered, patency of the microvasculature was maintained. Furthermore, ARA290 mitigated the innate inflammatory response, most notably tumor necrosis factor-alpha–mediated signaling. These findings correlated with long-term recovery of initially injured yet viable tissue components. In conclusion, ARA290 may be a promising therapeutic approach to prevent the conversion of partial- to full-thickness burn injuries. In a clinical setting, the decrease in burn depth and area would likely reduce the necessity for extensive surgical debridement as well as secondary wound closure by means of skin grafting. This use of ARA290 is consistent with its tissue-protective properties previously reported in other models of injury, such as myocardial infarction and hemorrhagic shock.

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Section: Discussionmentioning

confidence: 63%

Alternative erythropoietin-mediated signaling prevents secondary microvascular thrombosis and inflammation within cutaneous burns

Bohr

Patel

Shen

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…Increased circulating CD64 ϩ inflammatory Macs have been previously described in injury, and these more inflammatory Mac have altered function (41, 44 -46). We have previously reported that trauma patient M with high CD64 expression produce exaggerated amounts of the 26-kDa, cell-associated form of TNF-␣ with increased TNF-␣ mRNA stability (1,47). A recent report describes hM-CSF-differentiated PBMC Mac as producing higher TNF levels than M because of their increased TNF mRNA stability.…”

Section: Discussionmentioning

confidence: 98%

“…M any studies have demonstrated that monocyte (M ) 4 / macrophage (Mac) dysfunctions are pivotal in the development of the dysregulated inflammatory cytokine production typical of trauma patients who develop multiple organ failure and infectious complications (1)(2)(3)(4)(5)(6). Simultaneous with the often-exaggerated inflammatory response, these patients' M show depressed HLA-DR expression and a failure of Ag-presenting functions, which appears to be correlated with the development of T cell immunosuppression (7)(8)(9)(10)(11)(12)(13).…”

Section: M-csf Combined With Il-6 Inhibits M -To-idc Differentiation mentioning

confidence: 99%

Failure of Monocytes of Trauma Patients to Convert to Immature Dendritic Cells is Related to Preferential Macrophage-Colony-Stimulating Factor-Driven Macrophage Differentiation

De¹,

Laudański²,

Miller-Graziano

2003

The Journal of Immunology

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Following trauma, increased inflammatory monokine activation and depressed APC function can occur simultaneously. These contradictory monocyte (Mφ) dysfunctions could result if postinjury Mφ differentiation preferentially favored inflammatory macrophage (Mac) differentiation over development into the most potent APC, dendritic cells (DC). In this report, Mφ of trauma patients with a depressed MLR induction capacity are, for the first time, shown to be unable to differentiate in vitro to immature CD1a+ DC under the influence of GM-CSF and IL-4. Trauma patient Mφ that retained MLR-inducing capacity had a nonsignificant reduction in DC differentiation capacity. Only patient Mφ populations with depressed differentiation to immature DC (iDC) demonstrated depressed IL-12 and IL-15 production and a continued reduced MLR induction capacity. Neither increased IL-10 production nor decreased CD11c+ DC precursor numbers correlated with depressed Mφ-to-DC differentiation. Instead, these patients’ APC-dysfunctional Mφ populations had increased expression of inflammatory Mac phenotypes (CD64+, CD86low, HLA-DRlow) and up-regulated secretion of M-CSF. M-CSF combined with IL-6 inhibits Mφ-to-iDC differentiation and promotes Mφ-to-Mac differentiation by down-regulating GM-CSFR expression and increasing DC apoptosis. Both depressed GM-CSFR expression and increased Mφ iDC apoptosis, as well as increased expression of CD126 (IL-6R) and CD115 (M-CSFR), were detected in APC-defective patient Mφ. In vitro addition of anti-M-CSF enhanced the IL-4 plus GM-CSF-induced Mφ-to-DC differentiation of these patients. This suggests that, in trauma patients, enhanced Mφ-to-Mac differentiation with concomitant inhibited iDC development is partially due to increased circulating Mφ sensitivity to and production of M-CSF and contributes to postinjury immunoaberrations.

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“…Burn and trauma patients' MO accumulate large quantities of the membrane-associated form of TNF-␣ (mTNF-␣) while decreasing their secreted levels (7,8). Such postinjury increased MO TNF-␣ production is partially stimulated through the Toll-like receptors (TLR) by bacterial products and debris from damaged tissue (9)(10)(11).…”

Section: Introductionmentioning

confidence: 98%

“…We previously showed that aberrant MO to dendritic cell (DC) differentiation correlates with increased multiple organ dysfunction posttrauma (6). Excessive production of membrane-associated TNF-␣ and other inflammatory monokines are another hallmark of postinjury MO pathology (7,8).…”

Section: Introductionmentioning

confidence: 99%

Abnormal Pge2 Regulation of Monocyte TNF-?? Levels in Trauma Patients Parallels Development of a More Macrophage-Like Phenotype

Laudański

Brouxhon

et al. 2004

Shock

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Some trauma patients' monocytes (MO) increase TNF-alpha levels concomitant to augmenting production of the TNF-alpha inhibitor prostaglandin E2 (PGE2), suggesting posttrauma MO insensitivity to PGE2 effects. This study assesses additional posttrauma MO PGE2 insensitivity effects on altering TNF-alpha form (membrane versus secreted), down-regulating MO receptor expression, and depressing MO APC function. Posttrauma MO TNF-alpha insensitivity to exogenous and autocrine PGE2 correlated to accumulation of TNF-alpha primarily as a membrane-bound cytokine (mTNF-alpha). MO retention of mTNF-alpha correlated with unfavorable clinical outcomes and loss of antigen-presenting cell (APC) function as assessed by depressed MLR and dendritic cell (DC) differentiation. MO TNF-alpha sensitivity to down-regulation by IL-10 was retained, suggesting that PGE2-related functions are specifically altered in these patients' MO. Freshly isolated MO from all trauma patients had decreased expression of Toll-like receptor 4 (TLR4) for gram-negative bacteria. Exogenous PGE2 at high (10 (-6) M) or low (10 (-8) M) concentrations decreased normals' and further decreased APC-competent patients' MO TLR4 expression but had no effect on TLR2. Patients' APC-dysfunctional MO failed to further down-regulate their TLR4 expression in response to additional PGE2, demonstrating another form of PGE2 insensitivity. One of the primary MO prostaglandin receptors, eicosanoid receptor 4 (EP4), was decreased on patients' APC dysfunctional MO, suggesting that depressed EP4 expression could contribute to PGE2 insensitivity in patients' MO. The APC dysfunctional MO's dysregulation of TLR4 expression paralleled increased macrophage-like characteristics such as increased CD64 expression density, elevated mTNF-alpha production, and increased PGE2 levels. Increased PGE2 levels still decreased patients' MO APC functions but failed to depress either MO TLR4 expression or mTNF-alpha levels, suggesting differential involvement of EP receptors in postinjury PGE2-mediated effects.

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Increased monocyte TNF-α message stability contributes to trauma patients' increased TNF production

Abstract: Abstract:Post-trauma elevation of tumor necrosis factor a

Cited by 12 publications

References 50 publications

Alternative erythropoietin-mediated signaling prevents secondary microvascular thrombosis and inflammation within cutaneous burns

Alternative erythropoietin-mediated signaling prevents secondary microvascular thrombosis and inflammation within cutaneous burns

Failure of Monocytes of Trauma Patients to Convert to Immature Dendritic Cells is Related to Preferential Macrophage-Colony-Stimulating Factor-Driven Macrophage Differentiation

Abnormal Pge2 Regulation of Monocyte TNF-?? Levels in Trauma Patients Parallels Development of a More Macrophage-Like Phenotype

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