Oxidized Proteins Differentially Affect Maturation and Activation of Human Monocyte-Derived Cells

Abstract

In cancer, antigen-presenting cells (APC), including dendritic cells (DCs), take up and process proteins to mount adaptive antitumor immune responses. This often happens in the context of inflamed cancer, where reactive oxygen species (ROS) are ubiquitous to modify proteins. However, the inflammatory consequences of oxidized protein uptake in DCs are understudied. To this end, we investigated human monocyte-derived cell surface marker expression and cytokine release profiles when exposed to oxidized and native proteins. Seventeen proteins were analyzed, including viral proteins (e.g., CMV and HBV), inflammation-related proteins (e.g., HO1 and HMGB1), matrix proteins (e.g., Vim and Coll), and vastly in the laboratory used proteins (e.g., BSA and Ova). The multifaceted nature of inflammation-associated ROS was mimicked using gas plasma technology, generating reactive species cocktails for protein oxidation. Fourteen oxidized proteins led to elevated surface marker expression levels of CD25, CD40, CD80, CD86, and MHC-II as well as strongly modified release of IL6, IL8, IL10, IL12, IL23, MCP-1, and TNFα compared to their native counterparts. Especially IL8, heme oxygenase 2, and vimentin oxidation gave pronounced effects. Furthermore, protein kinase phospho-array studies in monocyte-derived cells pulsed with native vs. oxidized IL8 and insulin showed enhanced AKT and RSK2 phosphorylation. In summary, our data provide for the first time an overview of the functional consequences of oxidized protein uptake by human monocyte-derived cells and could therefore be a starting point for exploiting such principle in anticancer therapy in the future.

Medical Gas Plasma Technology Combines with Antimelanoma Therapies and Promotes Immune‐Checkpoint Therapy Responses

“…[ 72 ] Functional analysis of APCs after challenging with plasma‐oxidized tumor cells increased phagocyte activation, [ 73 ] followed by enhanced tumor material uptake [ 74 ] as seen in our study and interaction with T cells. [ 69 ] Moreover, a recent screening on a protein library pointed out to an inherent DAMP activity of oxidatively modified proteins generated by plasma treatment [ 75 , 76 ] comparable to advanced glycosylation end‐products on naturally occurring carbohydrates. [ 77 ] Following successful cross‐presentation and T cell priming, an inhospitable TME may preclude proper function of the expanded T cell repertoire.…”

Oxidant-modified amylin fibrils and aggregates alter the inflammatory profile of multiple myeloid cell types, but are non-toxic to islet β cells

“…During inflammation and oxidative stress, innate immune cells react to the presence of foreign materials by generating reactive oxidants, with the resulting oxidizing structures potentially leading to altered immunogenicity. Recently, we reported protein-specific changes in maturation and activation in DC in response to oxidized proteins, including insulin [ 47 ].…”

Exosomes target HBV-host interactions to remodel the hepatic immune microenvironment

“…Monocytes, the largest blood cells, and an essential immune system component, possess strong phagocytic and deformability abilities [ 72 , 73 ]. Changes in their proportion may indicate inflammation or disease, serving as a critical clinical reference index.…”