Human Myeloid-derived Suppressor Cells are Associated With Chronic Immune Suppression After Severe Sepsis/Septic Shock

Mathias, Brittany; Delmas, Amber L.; Ozrazgat‐Baslanti, Tezcan; Vanzant, Erin; Szpila, Benjamin E.; Mohr, Alicia M.; Moore, Frederick A.; Brakenridge, Scott C.; Brumback, Babette; Moldawer, Lyle L.; Efron, Philip A.

doi:10.1097/sla.0000000000001783

Cited by 197 publications

(239 citation statements)

References 38 publications

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“…Finally, emerging data support the concept that sepsis-associated immunosuppression of adaptive and innate immunity contributes to high mortality and morbidity during persistent sepsis (13,36). For example, septic patients who die show evidence of unresolved primary infection and acquisition of secondary, opportunistic infections, including reactivation of latent viruses (11,13).…”

Section: Discussionmentioning

confidence: 98%

“…Studies of newer approaches to immunoenhancement treatment of sepsis are under way (37). Our findings showing that sepsis-induced expansion of MDSCs promotes and maintains sepsis immunosuppression are relevant to these newer sepsis treatment strategies, since MDSCs suppress both innate and adaptive immunity (32,38), and MDSC numbers increase in blood of patients with sepsis (36, 39) and correlate with either early mortality or prolonged hospitalization (36). Moreover, elimination of MDSCs in tumor-bearing animals with FIG 10 NFI-A conditional knockout mice that had recovered from sepsis mount a normal inflammatory response to LPS challenge.…”

Section: Discussionmentioning

confidence: 99%

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Myeloid Cell-Specific Knockout of NFI-A Improves Sepsis Survival

et al. 2017

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Myeloid progenitor-derived suppressor cells (MDSCs) arise from myeloid progenitors and suppress both innate and adaptive immunity. MDSCs expand during the later phases of sepsis in mice, promote immunosuppression, and reduce survival. Here, we report that the myeloid differentiation-related transcription factor nuclear factor I-A (NFI-A) controls MDSC expansion during sepsis and impacts survival. Unlike MDSCs, myeloid cells with conditional deletion of the Nfia gene normally differentiated into effector cells during sepsis, cleared infecting bacteria, and did not express immunosuppressive mediators. In contrast, ectopic expression of NFI-A in myeloid progenitors from NFI-A myeloid cell-deficient mice impeded myeloid cell maturation and promoted immune repressor function. Importantly, surviving septic mice with conditionally deficient NFI-A myeloid cells were able to respond to challenge with bacterial endotoxin by mounting an acute inflammatory response. Together, these results support the concept of NFI-A as a master molecular transcriptome switch that controls myeloid cell differentiation and maturation and that malfunction of this switch during sepsis promotes MDSC expansion that adversely impacts sepsis outcome.KEYWORDS inflammation, sepsis immunosuppression, MDSCs, NFI-A, sepsis M yeloid progenitor-derived suppressor cells (MDSCs) represent a heterogenous population of immature myeloid cells that includes progenitors and precursors of monocytes/macrophages, granulocytes, and dendritic cells (1-3). MDSCs are generated under a variety of inflammatory and infection conditions (1, 2) and are best characterized by their immunosuppressive functions (4-6). They may also promote persistent inflammation and chronic infection with catabolism during chronic sepsis (7). MDSCs suppress both innate and adaptive immunity via production of immunosuppressive mediators and inhibition of T cell proliferation and activation (3,4,8). Phenotypically, murine MDSCs coexpress the myeloid differentiation markers Gr1 and CD11b, similarly to the Gr1 ϩ CD11b ϩ myeloid progenitors that arise under normal physiological conditions (2, 9). Unlike the immunosuppressive Gr1 ϩ CD11b ϩ cells (i.e., MDSCs), normal Gr1 ϩ CD11b ϩ cells can differentiate into competent innate immune cells (3). Elimination of MDSCs in tumor-bearing mice enhances antitumor immunity (10). Since MDSCs are "immature" cells that deviate from the standard path of differentiation, it has been suggested that arrested myeloid cell differentiation and maturation may be responsible for MDSC generation and immunorepression (2, 6). How immature myeloid cells lose their ability to differentiate and instead generate MDSCs remains unclear. Some studies, however, have suggested that MDSCs retain their potential to differentiate and mature but are trapped in a MDSC phenotype in the environmental milieu of chronic inflammation or growing tumors (1). In support of this, Kusmartsev et al. (10) reported that MDSCs from tumor-bearing mice could differentiate into macrophages and...

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Myeloid Cell-Specific Knockout of NFI-A Improves Sepsis Survival

et al. 2017

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“…We and others have now demonstrated that MDSC populations expand dramatically in patients with sepsis, and remain elevated for weeks, as long as patients remain critically ill[63, 64]. These immature myeloid cells are predominantly granulocytic, have profound suppressive properties, and at the transcriptional level, are proinflammatory and poor antigen presenters[64](Table 2).…”

Section: Pathophysiology Of Pics: Is Pics a Myelodysplastic Disease?mentioning

confidence: 99%

“…These immature myeloid cells are predominantly granulocytic, have profound suppressive properties, and at the transcriptional level, are proinflammatory and poor antigen presenters[64](Table 2). Importantly, patients who had the greatest elevation in MDSCs had either early mortality or prolonged hospitalizations; rapid resolution of MDSC numbers was associated with early discharge from the ICU[64]. …”

Section: Pathophysiology Of Pics: Is Pics a Myelodysplastic Disease?mentioning

confidence: 99%

Sepsis Pathophysiology, Chronic Critical Illness, and Persistent Inflammation-Immunosuppression and Catabolism Syndrome

Mira

Gentile²,

Mathias³

et al. 2017

Critical Care Medicine

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Objective To provide an appraisal of the evolving paradigms in the pathophysiology of sepsis, propose the evolution of a new phenotype of critically ill patients, its potential underlying mechanism, and its implications for the future of sepsis management and research. Design Literature search using PubMed, MEDLINE, EMBASE, and Google Scholar. Results Sepsis remains one of the most debilitating and expensive illnesses, and its incidence is not declining. What is changing is our definition(s), its clinical course, and how we manage the septic patient. Once thought to be predominantly a syndrome of over exuberant inflammation, sepsis is now recognized as a syndrome of aberrant host protective immunity. Earlier recognition and compliance with treatment bundles has fortunately led to a decline in multiple organ failure and in-hospital mortality. Unfortunately, more and more sepsis patients, especially the aged, are suffering chronic critical illness (CCI), rarely fully recover and often experience an indolent death. Patients with CCI often exhibit ‘a persistent inflammatory-immunosuppressive and catabolic syndrome’ or PICS, and it is proposed here that PICS contributes to many of these adverse clinical outcomes. The underlying cause of PICS is currently unknown, but there is increasing evidence that altered myelopoiesis, reduced effector T-cell function and expansion of immature myeloid-derived suppressor cells are all contributory. Conclusion Although newer therapeutic interventions are targeting the inflammatory, the immunosuppressive, and the protein catabolic responses individually, successful treatment of the septic patient with CCI and PICS may require a more complementary approach.

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“…The identification of these inflammatory mediators as suppressed in this model suggests that both chemokine and 149 growth factor production by the monocyte are functions that are also to some degree impaired. This would add further explanation to the decreased pathogen clearance seen in such patients, due to decreased leukocyte chemoattraction, as well as the lack of maturation and differentiation of new circulating leukocytes such as myeloid-derived suppressor cells 123,124 . Many pro-inflammatory cytokines are produced in response to NFκB activation, thus a reduction in all of these pro-inflammatory cytokine responses after IκK-16 was expected.…”

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confidence: 99%

The role and regulation of inhibitor of Kappa B Kinase in the impaired monocyte response.

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Human Myeloid-derived Suppressor Cells are Associated With Chronic Immune Suppression After Severe Sepsis/Septic Shock

Cited by 197 publications

References 38 publications

Myeloid Cell-Specific Knockout of NFI-A Improves Sepsis Survival

Myeloid Cell-Specific Knockout of NFI-A Improves Sepsis Survival

Sepsis Pathophysiology, Chronic Critical Illness, and Persistent Inflammation-Immunosuppression and Catabolism Syndrome

The role and regulation of inhibitor of Kappa B Kinase in the impaired monocyte response.

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