Reactive Carbonyls Are a Major Th2-Inducing Damage-Associated Molecular Pattern Generated by Oxidative Stress

Abstract

Oxidative stress is widespread and entwined with pathological processes, yet its linkage to adaptive immunity remains elusive. Reactive carbonyl (RC) adduction, a common feature of oxidative stress, has been shown to target proteins to the adaptive immune system. Because aldehydes are important mediators of carbonylation, we explored the immunomodulatory properties of model Ags modified by common bioactive aldehyde by-products of oxidative stress: 4-hydroxy-2-nonenal, malondialdehyde, and glycolaldehyde. Ag modification with all three aldehydes resulted in Ag-specific IgG1-dominated responses in adjuvant-free murine immunizations in an RC-dependent manner. The central role of RCs was confirmed, as their reduction into nonreactive groups abrogated all adaptive responses, despite the presence of other well-known aldehyde-driven adducts such as Nε-carboxymethyllysine and glycolaldehyde–pyridine. Moreover, Ag-specific Ab responses robustly correlated with the extent of RC adduction, regardless of the means of their generation. T cell responses mirrored the Th2-biased Ab isotypes by Ag-specific splenocyte production of IL-4, IL-5, and IL-13, but not IFN-γ. The RC-induced Th2 response was in sharp contrast to that induced by Th1/Th2 balanced or Th1-biasing adjuvants and was maintained in a range of mouse strains. In vitro studies revealed that RC adduction enhanced Ag presentation with Th2 polarization in the absence of conventional dendritic cell activation. Taken together, these data implicate commonly occurring RC as an important oxidation-derived Th2 immunomodulatory damage-associated molecular pattern with potentially important roles in health and disease.

Dry roasting enhances peanut-induced allergic sensitization across mucosal and cutaneous routes in mice

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Nitrosative Stress, Hypernitrosylation, and Autoimmune Responses to Nitrosylated Proteins: New Pathways in Neuroprogressive Disorders Including Depression and Chronic Fatigue Syndrome

“…malondialdehyde, may trigger activation of the TLR complex, particularly TLR-2 and TLR-4 [162][163][164]. MDA for example attacks proteins leading to the formation of reactive carbonyl adducts [165], which behave as potent DAMPS [166]. Protein carbonyl and radical species generated by TLR activation can react with molecular targets such as unsaturated membrane fatty acids causing structural and chemical changes generating oxidized phospholipids, oxidized low density lipoprotein, 4HNE and MDA adducts, protein carbonyls, and oxidized and degraded DNA [163,164].…”

Alzheimer's disease vaccine development: A new strategy focusing on immune modulation

“…Yet, this co-stimulatory signal may have contributed to exacerbate the AN1792's damaging inflammatory response, as aldehydes are regular oxidation products of polysorbate 80. That the aldehyde tucaresol favors a Th1 cytokine profile while that of Th2 cytokines seems to be unaffected (Hall and Rhodes, 2001) suggest that aldehydes affect only Th1 immunity; yet, under certain conditions, aldehydes enhance a T-cell proliferation biased to Th2 immunity, without DC activation (Moghaddam et al, 2011). That chemical modifications of the QS-21's aldehyde group result in a loss of its immunostimulatory properties as shown by the absence of an antibody response (Soltysik et al, 1995), supports the aldehyde role in Th2 immunity.…”