Loss of autophagy enhances MIF/macrophage migration inhibitory factor release by macrophages

Abstract

MIF (macrophage migration inhibitory factor [glycosylation-inhibiting factor]) is a pro-inflammatory cytokine expressed in multiple cells types, including macrophages. MIF plays a pathogenic role in a number of inflammatory diseases and has been linked to tumor progression in some cancers. Previous work has demonstrated that loss of autophagy in macrophages enhances secretion of IL1 family cytokines. Here, we demonstrate that loss of autophagy, by pharmacological inhibition or siRNA silencing of Atg5, enhances MIF secretion by monocytes and macrophages. We further demonstrate that this is dependent on mitochondrial reactive oxygen species (ROS). Induction of autophagy with MTOR inhibitors had no effect on MIF secretion, but amino acid starvation increased secretion. This was unaffected by Atg5 siRNA but was again dependent on mitochondrial ROS. Our data demonstrate that autophagic regulation of mitochondrial ROS plays a pivotal role in the regulation of inflammatory cytokine secretion in macrophages, with potential implications for the pathogenesis of inflammatory diseases and cancers.

Autophagy and autoimmunity

“…Inhibition of autophagy in antigen-presenting cells also leads to elevated IL-23 secretion as a consequential event of increased IL-1 β level [35]. Recently, autophagic regulation of mitochondrial reactive oxygen species (ROS) has been shown to control the secretion of another pro-inflammatory cytokine, macrophage migration inhibitory factor (MIF) [36], which aligns with previous studies and suggest defects in autophagy leads to increased pro-inflammatory cytokines secretion.…”

The role of mitochondrial ROS in antibacterial immunity

“…However, their influence may be either positive or negative, depending on the quantity of the mtROS involved. From the immunological viewpoint, the positive effects of mtROS are primarily based on their activating influence on antimicrobial immunity, while their negative effects, caused by their excessive production, result in the induction of autoinflammatory (van der Burgh & Boes, ) and autoimmune processes (Lee, Foote, et al, ; Lood et al, ). The formation of mtROS plays an important role in the development of the antiviral immunity including the production of proinflammatory cytokines by immune system cells (Kim et al, ).…”

Autophagy Inhibition Induces the Secretion of Macrophage Migration Inhibitory Factor (MIF) with Autocrine and Paracrine Effects on the Promotion of Malignancy in Breast Cancer

“…One of the consequences of blocking the autophagic pathway is an increase in ROS, due to the accumulation of damaged mitochondria [23]. MIF secretion in the 66cl4 cell line was due to increased ROS production caused by the inhibition of autophagy, since it could be prevented by treatment with an antioxidant ( Figure 3C).…”

“…It is known to be produced and secreted by numerous immune cells [34] and is also expressed in many endocrine, epithelial and endothelial cells [26]. In contrast to most cytokines, it is constitutively expressed, stored in intracellular vesicles and, since it does not have an endoplasmic reticulum (ER)-localizing sequence to enter the classical ER-Golgi complex pathway for secretion [35], it is secreted by an unconventional protein secretion pathway, known to involve ABC transporters [36], P115 [37] and the inhibition of autophagy [23] in LPS-activated macrophages. MIF has been implicated in several autoimmune and inflammatory disorders and, recently, it has been related to cancer progression due to the signaling pathways it activates [26].…”

“…So, despite controversies regarding the precise cellular target, CQ is one of the most widely used drugs to block autophagy at the autolysosomal degradation step, known to induce the accumulation of autophagosomes due to their decreased turnover [16] and to decrease the degradation of autophagic substrates [17].Recently, autophagy has been implicated in the regulation of protein secretion, either directly, in an unconventional protein secretion pathway termed secretory autophagy, or indirectly, by regulating the production of mitochondrial ROS which, in turn, regulate protein secretion, particularly the secretion of pro-inflammatory cytokines [18]. Regarding the latter, the pharmacological or genetic inhibition of autophagy has been shown to increase the secretion of IL-1β [19][20][21], , 20] and macrophage migration inhibitory factor (MIF) [23] in lipopolysaccharide (LPS)-treated macrophages and of in cancer epithelial cells. Importantly for cancer therapy, many of these cytokines have been shown to have pro-tumorigenic effects in cancer cells through the activation of pro-tumorigenic signaling pathways, CSC maintenance and the promotion of epithelial to mesenchymal transition (EMT) in different types of cancer [10].…”