Myeloid Commitment Shifts Toward Monocytopoiesis After Thermal Injury and Sepsis

Santangelo, Steve; Gamelli, Richard L.; Shankar, Ravi

doi:10.1097/00000658-200101000-00015

Cited by 74 publications

(77 citation statements)

References 29 publications

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“…A postinjury increase in myeloid M-CSFR expression has also been recently reported in a murine burn model (2). Increased M-CSFR and decreased GM-CSFR expression are also characteristics of CD34 ϩ stem cells that shifted from DC to Mac differentiation after M-CSF plus IL-6 culture (23).…”

Section: Discussionmentioning

confidence: 63%

“…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%

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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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Section: Discussionmentioning

confidence: 63%

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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“…Immune function after major trauma has been well studied and is known to go awry due, in part, to the overproduction of numerous proinflammatory mediators (2)(3)(4)(5), alterations in the production of granulocyte and monocyte progenitors (6,7), and increased production of immunomodulatory cytokines, including IL-4, IL-10, and TGF-␤ (4, 8 -10). Investigations over the past two decades have provided new insight into the roles of macrophages, dendritic cells, and T lymphocytes in regulating immunity during injury and sepsis (11)(12)(13).…”

mentioning

confidence: 99%

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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“…Pioneer work by Santangelo et al documented signs of myelosuppression and a shift toward monopoiesis at expense of granulopoiesis in murine models of severe sepsis. 9 Recently, it is becoming increasingly evident that causes of neutropenia in sepsis include not only bacterial consumption and apoptosis, 10 but also decreased neutrophil production by the bone marrow, such as defective generation of myeloid progenitors at the HSC level, as shown by our group. 3 The ability of IFN-␥ to suppress G-CSF response by inducing the signal transduction antagonist SOCS3 can also explain why septic patients are neutropenic despite normal levels of G-CSF or are insensitive to G-CSF treatment.…”

mentioning

confidence: 70%

“…9 This smaller dosage regimen, which achieved a high rate of ITI within a time frame similar to that of the high dosage (on average ϳ 1 year from onset), was highly appealing due to decreased cost and patient acceptability.…”

mentioning

confidence: 95%

When IFN interferes with cell fate

Carlesso

2012

Blood

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Myeloid Commitment Shifts Toward Monocytopoiesis After Thermal Injury and Sepsis

Abstract: The data validate the premise that enhanced monocytopoiesis in thermal injury and sepsis results from an imbalance in myelopoiesis that is driven by the increased expression of macrophage colony-stimulating factor receptor.

Cited by 74 publications

References 29 publications

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

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

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

When IFN interferes with cell fate

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