Background/Purpose:

During inflammation and tissue damage, pathogens as well as dying cells are ingested by different phagocytes such as macrophages and dendritic cells. The uptake of particles and subsequent presentation of derived antigens by antigen presenting cells (APC) are key events in the initiation of an adaptive immune response. Thus, both the nature and the activation state of the respective phagocyte determine the resulting immune response ranging from specific immunity to tolerance. However, defects and alterations of these processes are associated with chronic inflammation and autoimmunity. Specific lipid oxidation products, generated by the enzyme 12/15-lipoxygenase (12/15-LO) were implicated in the active resolution of inflammation and limitation of inflammation-associated tissue damage. In this study, we investigated the potential role of enzymatic lipid oxidation by 12/15-LO during initiation of an adaptive immune response and the maintenance of self-tolerance.

Methods:

We studied both the clearance of AC and pathogens, as well as the maturation and function of monocyte-derived, antigen-presenting phagocytes in wildtype and 12/15-LO -/- animals in vitro and in vivo, respectively.

Results:

We observed a pivotal role of 12/15-LO in the maintenance of self-tolerance as aged 12/15-LO-deficient mice spontaneously developed autoimmune features indicating a break of self-tolerance. Moreover, a loss of 12/15-LO resulted in an exacerbation of a murine disease model of experimental autoimmune encephalomyelitis (EAE), which resembles clinical and pathological hallmarks of human multiple sclerosis.

Consistently, 12/15-LO -/- mice showed a disturbed clearance of AC under inflammatory conditions, with a clear shift of phagocytosis towards pro-inflammatory antigen-presenting cells. In addition, we could detect a marked expression of 12/15-LO in in vitro-generated bone marrow-derived dendritic cells (BMDC). Interestingly, BMDC isolated from 12/15-LO -/- mice presented an increased expression of co-stimulatory molecules on their surface, accompanied by an altered pro-inflammatory cytokine profile. Under inflammatory conditions, the uptake of AC-derived model-antigens by APC from 12/15-LO -/- mice resulted in an increased antigen presentation and subsequent T cell activation, both in vitro and in vivo. By adding 12/15-LO-generated phospholipid oxidation products, we were, in turn, able to restore an anti-inflammatory clearance of AC in vitro and in vivo, down-regulate co-stimulatory markers expressed by APC and, thereby, limit T cell activation in vitro.

Conclusion:

Together, these data indicate a potential regulatory role of enzymatic lipid oxidation by 12/15-LO during the initiation of an adaptive immune response by both orchestrating a cell- and context-specific clearance of antigens by different phagocyte subsets and regulating the maturation and activation status of the respective APC.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/enzymatic-lipid-oxidation-contributes-to-the-maintenance-of-self-tolerance-by-regulating-antigen-clearance-and-dendritic-cell-function/