Abstract
Endotoxin tolerance represents a safeguard mechanism for preventing detrimental prolonged inflammation and exaggerated immune/inflammatory responses from innate immune cells to recurrent harmless pathogens. On the other hand, excessive immune tolerance can contribute to pathological immunosuppression, e.g., as present in sepsis. Monocyte activation is accompanied by intracellular metabolic rearrangements that are reportedly orchestrated by the metabolic signaling node mTORC1. mTORC1-dependent metabolic re-wiring plays a major role in monocyte/macrophage polarization, but whether mTORC1 participates in the induction of endotoxin tolerance and other immune adaptive programs, such as immune training, is not clear. This connection has been difficult to test in the past due to the lack of appropriate models of human endotoxin tolerance allowing for the genetic manipulation of mTORC1. We have addressed this shortcoming by investigating monocytes from tuberous sclerosis (TSC) patients that feature a functional loss of the tumor suppressor TSC1/2 and a concomitant hyperactivation of mTORC1. Subjecting these cells to various protocols of immune priming and adaptation showed that the TSC monocytes are not compromised in the induction of tolerance. Analogously, we find that pharmacological mTORC1 inhibition does not prevent endotoxin tolerance induction in human monocytes. Interestingly, neither manipulation affected the capacity of activated monocytes to switch to increased lactic fermentation. In sum, our findings document that mTORC1 is unlikely to be involved in the induction of endotoxin tolerance in human monocytes and argue against a causal link between an mTORC1-dependent metabolic switch and the induction of immune tolerance.
Highlights
Innate immune cells of the myeloblastic lineage constitute the first line of defense against infection and tissue breakdown in trauma
In order to test the role of mTOR containing complex 1 (mTORC1) on the plasticity and the adaptation properties of human monocytes, we investigated, side by side, monocytes from tuberous sclerosis (TSC) patients and healthy donors
Our data argue against a dominant role of mTORC1 in this process as the increase in lactic acid production was indistinguishable in control and TSC monocytes or in the presence of mTORC1 inhibition
Summary
Innate immune cells of the myeloblastic lineage constitute the first line of defense against infection and tissue breakdown in trauma. Upon identifying, spotting, tracking, or engulfing pathogens, pathogen-associated molecular patterns (PAMPs), or damage-associated molecular patterns, the myeloblastic cells elicit a cascade of inflammatory and immune responses mediated by the release of cytokine cocktails and eventually the direct presentation of antigen to lymphocytes. Due to their unique ability to recognize and rank infectious or traumatic triggers, the innate immune cells dictate the quality and the intensity of the host response and the course of an infection episode. In a process known as immune training, the activated monocytes re-configure their response toward ensuing inflammatory cues in the long term via PAMP-induced changes in the epigenome [1, 2]
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