Mortality in human sepsis is associated with downregulation of Toll-like receptor 2 and CD14 expression on blood monocytes

Schaaf, Bernhard; Luitjens, K; Goldmann, Torsten; Bremen, Tobias Van; Sayk, Friedhelm; Dodt, Christoph; Dalhoff, K; Droemann, Daniel

doi:10.1186/1746-1596-4-12

Cited by 56 publications

(51 citation statements)

References 36 publications

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“…While TLR2 expression remained relatively unchanged on monocytes from ND individuals in response to B. pseudomallei stimulation, there was a trend for decreased TLR2 expression on monocytes from both PC-T2D and WC-T2D individuals. The pattern of decreased TLR2 and CD14 levels on monocytes from diabetic individuals in the present study is consistent with the profile described for patients with severe sepsis, although no comparisons have been made between diabetic and nondiabetic patients (9,49,62). In addition, peripheral blood samples from the sepsis studies were collected from patients following commencement of antimicrobial therapy after hospital admission, making it difficult to draw parallels to the early changes in TLR expression measured in our whole-blood stimulation assay.…”

Section: Discussionsupporting

confidence: 58%

“…Changes in CD14 expression may reflect internalization of membrane-bound CD14 (39) or increased shedding of surface CD14 (48). Decreased membrane CD14 on monocytes, described as monocyte hypore-sponsiveness, has been shown to correlate with sepsis severity (9,49). Our findings of decreased surface expression of CD14 on monocytes from T2D individuals suggest alterations in monocyte functional capacity following exposure to B. pseudomallei may contribute to more severe disease progression in T2D individuals.…”

Section: Discussionsupporting

confidence: 45%

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Burkholderia pseudomallei Triggers Altered Inflammatory Profiles in a Whole-Blood Model of Type 2 Diabetes-Melioidosis Comorbidity

et al. 2012

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ABSTRACTMelioidosis is a potentially fatal disease caused by the bacteriumBurkholderia pseudomallei. Type 2 diabetes (T2D) is the most common comorbidity associated with melioidosis.B. pseudomalleiisolates from melioidosis patients with T2D are less virulent in animal models than those from patients with melioidosis and no identifiable risk factors. We developed anex vivowhole-blood assay as a tool for comparison of early inflammatory profiles generated by T2D and nondiabetic (ND) individuals in response to aB. pseudomalleistrain of low virulence. Peripheral blood from individuals with T2D, with either poorly controlled glycemia (PC-T2D [n= 6]) or well-controlled glycemia (WC-T2D [n= 8]), and healthy ND (n= 13) individuals was stimulated withB. pseudomallei. Oxidative burst, myeloperoxidase (MPO) release, expression of pathogen recognition receptors (TLR2, TLR4, and CD14), and activation markers (CD11b and HLA-DR) were measured on polymorphonuclear (PMN) leukocytes and monocytes. Concentrations of plasma inflammatory cytokine (interleukin-6 [IL-6], IL-12p70, tumor necrosis factor alpha [TNF-α], monocyte chemoattractant protein 1 [MCP-1], IL-8, IL-1β, and IL-10) were also determined. Following stimulation, oxidative burst and MPO levels were significantly elevated in blood from PC-T2D subjects compared to controls. Differences were also observed in expression of Toll-like receptor 2 (TLR2), CD14, and CD11b on phagocytes from T2D and ND individuals. Levels of IL-12p70, MCP-1, and IL-8 were significantly elevated in blood from PC-T2D subjects compared to ND individuals. Notably, differential inflammatory responses of PC-T2D, WC-T2D, and ND individuals toB. pseudomalleioccur independently of bacterial load and confirm the efficacy of this model of T2D-melioidosis comorbidity as a tool for investigation of dysregulated PMN and monocyte responses toB. pseudomalleiunderlying susceptibility of T2D individuals to melioidosis.

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Section: Discussionsupporting

confidence: 58%

Section: Discussionsupporting

confidence: 45%

Burkholderia pseudomallei Triggers Altered Inflammatory Profiles in a Whole-Blood Model of Type 2 Diabetes-Melioidosis Comorbidity

et al. 2012

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“…However, in this case, CD14 was suggested to mediate this cascade. In light of our data, it is possible that CD16 may act as an important pathway to activate a Syk-dependent TRIF pathway, especially under conditions when CD14 is downregulated as has been reported for sepsis monocytes (60).…”

Section: Discussionmentioning

confidence: 90%

CD16 Regulates TRIF-Dependent TLR4 Response in Human Monocytes and Their Subsets

Shalova

Kajiji

Lim

et al. 2012

The Journal of Immunology

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Blood monocytes recognize Gram-negative bacteria through the TLR4, which signal via MyD88- and TRIF-dependent pathway to trigger an immune-inflammatory response. However, a dysregulated inflammatory response by these cells often leads to severe pathologies such as sepsis. We investigated the role of CD16 in the regulation of human monocyte response to Gram-negative endotoxin and sepsis. Blood monocytes from sepsis patients demonstrated an upregulation of several TRIF-dependent genes as well as a selective expansion of CD16-expressing (CD16+) monocytes. Gene expression and biochemical studies revealed CD16 to regulate the TRIF-dependent TLR4 pathway in monocytes by activating Syk, IFN regulatory factor 3, and STAT1, which resulted in enhanced expression of IFNB, CCL5, and CXCL10. CD16 also upregulated the expression of IL-1R–associated kinase M and IL-1 receptor antagonist, which are negative regulators of the MyD88-dependent pathway. CD16 overexpression or small interfering RNA knockdown in monocytes confirmed the above findings. Interestingly, these results were mirrored in the CD16+ monocyte subset isolated from sepsis patients, providing an in vivo confirmation to our findings. Collectively, the results from the current study demonstrate CD16 as a key regulator of the TRIF-dependent TLR4 pathway in human monocytes and their CD16-expressing subset, with implications in sepsis.

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“…It has been described that an in vivo LPS challenge induces hyporesponsiveness to following in vivo or ex vivo LPS challenges. The biochemical mechanisms accounting for this hyporesponsiveness have been demonstrated to involve negative regulators such as IRAK-M, SOCS-1, SHIP, ST2 and IL-10 [2,3,[12][13][14][15][16][17][18] and downregulation of CD14 [19].…”

Section: Introductionmentioning

confidence: 99%

Characterization of inflammation and immune cell modulation induced by low-dose LPS administration to healthy volunteers

et al. 2014

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Human in vivo models of systemic inflammation are used to study the physiological mechanisms of inflammation and the effect of drugs and nutrition on the immune response. Although in vivo lipopolysaccharide (LPS) challenges have been applied as methodological tool in clinical pharmacology studies, detailed information is desired on dose-response relationships, especially regarding LPS hyporesponsiveness observed after low-dose in vivo LPS administration. A study was performed to assess the in vivo inflammatory effects of low intravenous LPS doses, and to explore the duration of the induced LPS hyporesponsiveness assessed by subsequent ex vivo LPS challenges. This was a randomized, double-blind, placebo-controlled study with single ascending low doses of LPS (0.5, 1 and 2 ng/kg body weight) administered to healthy male volunteers (3 cohorts of 8 subjects, LPS:placebo 6:2). The in vivo inflammatory response was assessed by measurement of cytokines and CRP. Ex vivo LPS challenges were performed (at −2, 6, 12, 24, 48 and 72 hours relative to in vivo LPS administration) to estimate the duration and magnitude of LPS hyporesponsiveness by assessment of cytokine release (TNF-α, IL-1β, IL-6, IL-8). LPS administration dose-dependently increased body temperature (+1.5°C for 2 ng/kg LPS), heart rate (+28 bpm for 2 ng/kg LPS), CRP and circulating cytokines which showed clearly distinctive increases from placebo already at the lowest LPS dose level tested (0.5 ng/kg, contrast for timeframe 0-6 hours: TNF-α +413%, IL-6 +288%, IL-8 +254%; all p ≤ 0.0001). In vivo LPS administration dose-dependently induced a period of hyporesponsiveness in the ex vivo LPS-induced cytokine release (IL-1β, IL-6 and TNF-α), with maximal hyporesponsiveness observed at 6 hours, lasting no longer than 12 hours. For IL-6 and IL-8, indications for immune cell priming were observed. We demonstrated that an in vivo LPS challenge, with LPS doses as low as 0.5 ng/kg, elicits a cytokine response that is clearly distinctive from baseline cytokine levels. This study expanded the knowledge about the dose-effect relationship of LPS-induced hyporesponsiveness. As such, the low-dose LPS challenge has been demonstrated to be a feasible methodological tool for future clinical studies exploring pharmacological or nutritional immune-modulating effects.

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Mortality in human sepsis is associated with downregulation of Toll-like receptor 2 and CD14 expression on blood monocytes

Cited by 56 publications

References 36 publications

Burkholderia pseudomallei Triggers Altered Inflammatory Profiles in a Whole-Blood Model of Type 2 Diabetes-Melioidosis Comorbidity

Burkholderia pseudomallei Triggers Altered Inflammatory Profiles in a Whole-Blood Model of Type 2 Diabetes-Melioidosis Comorbidity

CD16 Regulates TRIF-Dependent TLR4 Response in Human Monocytes and Their Subsets

Characterization of inflammation and immune cell modulation induced by low-dose LPS administration to healthy volunteers

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