DNA-Containing Immunocomplexes Promote Inflammasome Assembly and Release of Pyrogenic Cytokines by CD14 ⁺ CD16 ⁺ CD64 ^high CD32 ^low Inflammatory Monocytes from Malaria Patients

Abstract

High levels of circulating immunocomplexes (ICs) are found in patients with either infectious or sterile inflammation. We report that patients with either Plasmodium falciparum or Plasmodium vivax malaria have increased levels of circulating anti-DNA antibodies and ICs containing parasite DNA. Upon stimulation with malaria-induced ICs, monocytes express an NF-κB transcriptional signature. The main source of IC-induced proinflammatory cytokines (i.e., tumor necrosis factor alpha [TNF-α] and interleukin-1β [IL-1β])in peripheral blood mononuclear cells from acute malaria patients was found to be a CD14+ CD16 (FcγRIIIA)+ CD64 (FcγRI)high CD32 (FcγRIIB)low monocyte subset. Monocytes from convalescent patients were predominantly of the classical phenotype (CD14+ CD16−) that produces high levels of IL-10 and lower levels of TNF-α and IL-1β in response to ICs. Finally, we report a novel role for the proinflammatory activity of ICs by demonstrating their ability to induce inflammasome assembly and caspase-1 activation in human monocytes. These findings illuminate our understanding of the pathogenic role of ICs and monocyte subsets and may be relevant for future development of immunity-based interventions with broad applications to systemic inflammatory diseases.

A Functional Role for Antibodies in Tuberculosis

“…Recent studies have shown that Abs can activate the inflammasome in the context of malaria (Hirako et al, 2015) and autoimmune disease (Muller-Calleja et al, 2015) and that inflammasome activation may play an important role in TB infection (Briken et al, 2013). Treatment of Mtb-infected MDM with pooled Ltb as compared to Atb Abs increased the formation of perinuclear Apoptosis-associated Speck-like protein containing a Caspase Activation and Recruitment Domain (ASC) aggregates (Mishra et al, 2010), a measure of inflammasome activation (Figure 4C and D, p=0.0226 and 0.0180).…”

“…The impact on inflammasome activation is particularly provocative in light of recent studies showing that circulating immune complexes containing Plasmodium spp. DNA (Hirako et al, 2015) or phospholipid-specific Abs can activate the inflammasome in monocytes (Muller-Calleja et al, 2015; Prinz et al, 2011). Moreover, in some TB studies, inflammasome activation has been linked to bacterial control (Carlsson et al, 2010; Eklund et al, 2014; Mishra et al, 2010; Pontillo et al, 2013).…”

Malaria inflammation by xanthine oxidase‐produced reactive oxygen species

“…Previous reports have identified that Plasmodium infection activates the inflammasome in human patients (Ataide et al , ; Hirako et al , ); however, studies in vitro needed an additional exogenous signal 1 for the production of IL‐1β that was added in the form of LPS, which is a bacterial product not present during malaria (Ataide et al , ; Kalantari et al , ; Hirako et al , ). Our results identify extracellular ROS, which are characteristic of malaria, as an effective signal 1 for the activation of the inflammasome in macrophages and provide a physiological explanation for those previous observations.…”

Cytosolic Recognition of Microbes and Pathogens: Inflammasomes in Action

“…Polymorphisms in the genes encoding NLRP1 and IL-1␤ are associated with more severe P. vivax infection, whereas a polymorphism in the gene encoding IL-18 is associated with protection against P. vivax-induced anemia (293). Further, patients infected with Plasmodium have elevated levels of proinflammatory cytokines, including tumor necrosis factor (TNF) and IL-1␤ (294); the level of IL-1␤ in patients correlates with disease severity, particularly for cerebral malaria (295).…”