Tissue Immune Cells Fuel Obesity-Associated Inflammation in Adipose Tissue and Beyond

Li, Rui; Nikolajczyk, Barbara S.

doi:10.3389/fimmu.2019.01587

Cited by 223 publications

(203 citation statements)

References 159 publications

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“…The critical role of CD8 T cells in the initiation and propagation of adipose tissue inflammation and remodeling with obesity is becoming clear and appears to involve intricate crosstalk between T cells, adipocytes, and M1 macrophages via the production of inflammatory cytokines like IFNγ, TNFα, and IL-6. [42][43][44][45] Therefore, in response to HFD administration, an early influx of CD8 T cells into white adipose tissue contributes to the development of classic, systemic hallmarks of obesity.…”

Section: Obesity Drives a Pro-inflammatory Host Environmentmentioning

confidence: 99%

Obesity and CD8 T cell metabolism: Implications for anti‐tumor immunity and cancer immunotherapy outcomes

Turbitt

Rosean

Weber

et al. 2020

Immunological Reviews

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Obesity is an established risk factor for many cancers and has recently been found to alter the efficacy of T cell–based immunotherapies. Currently, however, the effects of obesity on immunometabolism remain unclear. Understanding these associations is critical, given the fact that T cell metabolism is tightly linked to effector function. Thus, any obesity‐associated changes in T cell bioenergetics are likely to drive functional changes at the cellular level, alter the metabolome and cytokine/chemokine milieu, and impact cancer immunotherapy outcomes. Here, we provide a brief overview of T cell metabolism in the presence and absence of solid tumor growth and summarize current literature regarding obesity‐associated changes in T cell function and bioenergetics. We also discuss recent findings related to the impact of host obesity on cancer immunotherapy outcomes and present potential mechanisms by which T cell metabolism may influence therapeutic efficacy. Finally, we describe promising pharmaceutical therapies that are being investigated for their ability to improve CD8 T cell metabolism and enhance cancer immunotherapy outcomes in patients, regardless of their obesity status.

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Section: Obesity Drives a Pro-inflammatory Host Environmentmentioning

confidence: 99%

Obesity and CD8 T cell metabolism: Implications for anti‐tumor immunity and cancer immunotherapy outcomes

Turbitt

Rosean

Weber

et al. 2020

Immunological Reviews

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“…We show that obesity associated changes primes the DC precursors with persistent p38 activation and expansion that could be reversed by pharmacological inhibition of p38 activity. This suggest that alterations of DC supply chain contribute to the chronic lowgrade inflammation associated with obesity (46,47).…”

Section: Discussionmentioning

confidence: 96%

Dendritic Cell-Restricted Progenitors Contribute to Obesity-Associated Airway Inflammation via Adam17-p38 MAPK-Dependent Pathway

et al. 2020

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Proliferation of dendritic cell (DC)-restricted progenitor cells in bone marrow compartment is tightly regulated at steady state and responds to multiple tissue-specific triggers during disturbed homeostasis such as obesity. DCs in the lung stem from a rapidly dividing DC-restricted progenitor cells and are effective at generating adaptive immune responses in allergic airway inflammation. Precisely, how DC-restricted progenitor expansion and differentiation are influenced by airway inflammation to maintain constant supply of myeloid DCs is poorly understood. Here we show that a high fat diet (HFD) induces oxidative stress and accelerates the expansion of DC-restricted progenitor cells in bone marrow and correlates with persistent induction of p38 mitogen activated protein kinase (MAPK), which is blocked with a selective p38α/β MAPK inhibitor. Mice fed a HFD and sensitized to inhaled allergen house dust mite (HDM) led to alterations of DC-restricted progenitor cells that were characterized by increased expansion and seeding of lung DCs in airway inflammation. Mechanistically, we establish that the expansion induced by HFD dysregulates the expression of a disintegrin and metallopeptidase domain 17 (Adam17) and is required for p38 MAPK activation in DC-restricted progenitors. These results demonstrates that obesity produces persistent changes in DC precursors and that elevation of Adam17 expression is tightly coupled to p38 MAPK and is a key driver of proliferation. Altogether, these data provide phenotypic and mechanistic insight into dendritic cell supply chain in obesity-associated airway inflammation.

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“…Obesity-driven changes of the adipose tissue monocytes/macrophages alters the secretion of proinflammatory cytokines which contributes to the progression of inflammation and the development of insulin resistance (19,20). Tumor necrosis factor-α (TNF-α), which is overexpressed in obese humans and rodents, plays a central role in metabolic inflammation and insulin resistance.…”

Section: Discussionmentioning

confidence: 99%

Neutral sphingomyelinase 2 regulates inflammatory responses in monocytes/macrophages induced by TNF-α

Al-Rashed

Ahmad

Thomas

et al. 2020

Preprint

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Obesity is associated with elevated levels of TNF-α and proinflammatory CD11c monocytes /macrophages. TNF-α mediated dysregulation in the plasticity of monocytes/macrophages is concomitant with pathogenesis of several inflammatory diseases, including metabolic syndrome, but the underlying mechanisms are incompletely understood. Since neutral sphingomyelinase 2 (nSMase2; product of the sphingomyelin phosphodiesterase 3 gene, SMPD3) is a key enzyme for ceramide production involved in inflammation, we investigated whether nSMase2 contributed to the inflammatory changes in the monocytes/macrophages induced by TNF-α. In this study, we demonstrate that the disruption of nSMase activity in monocytes/macrophages either by chemical inhibitor GW4869 or small interfering RNA (siRNA) against SMPD3 results in defects in the TNF-α mediated expression of CD11c. Furthermore, blockage of nSMase in monocytes/macrophages inhibited the secretion of inflammatory mediators IL-1b and MCP-1. In contrast, inhibition of acid SMase (aSMase) activity did not attenuate CD11c expression or secretion of IL-1b and MCP-1. TNF-α-induced phosphorylation of JNK, p38 and NF-κB was also attenuated by the inhibition of nSMase2. Moreover, NF-kB/AP-1 activity was blocked by the inhibition of nSMase2. SMPD3 was elevated in PBMCs from obese individuals and positively corelated with TNF-α gene expression. These findings indicate that nSMase2 acts, at least in part, as a master switch in the TNF-α mediated inflammatory responses in monocytes/macrophages.

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Tissue Immune Cells Fuel Obesity-Associated Inflammation in Adipose Tissue and Beyond

Cited by 223 publications

References 159 publications

Obesity and CD8 T cell metabolism: Implications for anti‐tumor immunity and cancer immunotherapy outcomes

Obesity and CD8 T cell metabolism: Implications for anti‐tumor immunity and cancer immunotherapy outcomes

Dendritic Cell-Restricted Progenitors Contribute to Obesity-Associated Airway Inflammation via Adam17-p38 MAPK-Dependent Pathway

Neutral sphingomyelinase 2 regulates inflammatory responses in monocytes/macrophages induced by TNF-α

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