Signal-Strength and History-Dependent Innate Immune Memory Dynamics in Health and Disease

Geng, Shuo; Pradhan, Kisha; Li, Liwu

doi:10.1007/164_2021_485

Cited by 6 publications

(2 citation statements)

References 114 publications

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“…TNF-α and IL-6 are blood biomarkers that are increased after TBI [ 6 ], and we indeed confirm the increased level of IL-6 in the plasma of TBI patients. The fact that herein we found that stimulated monocytes produce less IL-6 and TNF-α could indicate that TBI have induced an exhausted state of monocytes [ 76 ], with a reduced ability to drive a pro-inflammatory response, thus contributing to post-injury complications, such as infections. On the other hand, the elevated pro-inflammatory cytokines found in the blood could derive from other cells, such as from injured brain cells (i.e.…”

Section: Discussionmentioning

confidence: 99%

Systemic immune response in young and elderly patients after traumatic brain injury

Magatti,

Pischiutta,

Ortolano

et al. 2023

Immun Ageing

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Background Traumatic brain injury (TBI) is a leading cause of death and long-term disability worldwide. In addition to primary brain damage, systemic immune alterations occur, with evidence for dysregulated immune responses in aggravating TBI outcome and complications. However, immune dysfunction following TBI has been only partially understood, especially in the elderly who represent a substantial proportion of TBI patients and worst outcome. Therefore, we aimed to conduct an in-depth immunological characterization of TBI patients, by evaluating both adaptive (T and B lymphocytes) and innate (NK and monocytes) immune cells of peripheral blood mononuclear cells (PBMC) collected acutely (< 48 h) after TBI in young (18–45 yo) and elderly (> 65 yo) patients, compared to age-matched controls, and also the levels of inflammatory biomarkers. Results Our data show that young respond differently than elderly to TBI, highlighting the immune unfavourable status of elderly compared to young patients. While in young only CD4 T lymphocytes are activated by TBI, in elderly both CD4 and CD8 T cells are affected, and are induced to differentiate into subtypes with low cytotoxic activity, such as central memory CD4 T cells and memory precursor effector CD8 T cells. Moreover, TBI enhances the frequency of subsets that have not been previously investigated in TBI, namely the double negative CD27- IgD- and CD38-CD24- B lymphocytes, and CD56dim CD16- NK cells, both in young and elderly patients. TBI reduces the production of pro-inflammatory cytokines TNF-α and IL-6, and the expression of HLA-DM, HLA-DR, CD86/B7-2 in monocytes, suggesting a compromised ability to drive a pro-inflammatory response and to efficiently act as antigen presenting cells. Conclusions We described the acute immunological response induced by TBI and its relation with injury severity, which could contribute to pathologic evolution and possibly outcome. The focus on age-related immunological differences could help design specific therapeutic interventions based on patients’ characteristics.

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Section: Discussionmentioning

confidence: 99%

Systemic immune response in young and elderly patients after traumatic brain injury

Magatti,

Pischiutta,

Ortolano

et al. 2023

Immun Ageing

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“…Emerging studies reveal the presence of innate immune memory, a complex process during which innate leukocytes adopt altered activation states depending upon the signal strength and history of challenges [ 1 ]. Basic and translational studies suggest that monocyte memory dynamics occur in both human and murine monocytes, with shared features of altered activation dynamics ranging from priming, tolerance to exhaustions.…”

Section: Introductionmentioning

confidence: 99%

Comparative analyses of monocyte memory dynamics from mice to humans

Geng

2023

Inflamm. Res.

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Background Innate monocytes can adopt dynamic “memory” states ranging from low-grade inflammation to pathogenic exhaustion, dependent upon signal strength and history of challenges. Low-grade inflammatory monocytes facilitate the pathogenesis of chronic inflammatory diseases, while exhausted monocytes drive the pathogenesis of severe sepsis. Although clinical and basic studies suggest the conservation of key features of exhausted monocytes from human and murine sepsis, systems analyses of monocyte exhaustion among human and murine monocytes are lacking. Methods We performed cross examination of septic monocytes scRNAseq data recently collected from human sepsis patients as well as experimental septic mice, in reference to monocytes experimentally exhausted in vitro. Furthermore, we performed pseudo-time analyses of in vitro programmed monocytes following prolonged challenges causing either low-grade inflammation or exhaustion. Additional comparative analyses of low-grade inflammatory monocytes were performed with scRNAseq data from selected human patients with chronic low-grade inflammatory diseases. Results Our systems analyses reveal key features of monocyte exhaustion including reduced differentiation, pathogenic inflammation and immune suppression that are highly conserved in human and murine septic monocytes, and captured by in vitro experimental exhaustion. Pseudo-time analyses reveal that monocytes initially transition into a less-differentiated state with proliferative potential. The expansion of proliferative monocytes can be observed not only in experimentally challenged monocytes, but also in tissues of murine sepsis and human septic blood. We observed that monocytes similarly transition into the less-differentiated state when challenged with a subclinical dose endotoxin under chronic inflammatory conditions. Instead of being exhausted, monocytes with prolonged challenges with super-low dose endotoxin bifurcate into the low-grade inflammatory immune-enhancing or the chemotactic/adhesive state, often see in atherosclerosis or auto-immune diseases. Conclusions Key features of monocyte memory dynamics are identified and conserved in human and murine monocytes, which can be captured by prolonged challenges of innate signals with varying signal strength.

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