IL-1 Family Cytokine Pathways Underlying NAFLD: Towards New Treatment Strategies

Abstract

Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide. Pathways responsible for the activation of IL-1 family cytokines are key in the development of NAFLD but underlying mechanisms are not fully understood. Many studies have focused on the inflammasome-caspase-1 pathway and have shown that this pathway is an important inducer of inflammation in NAFLD. However, this pathway is not solely responsible for the activation of proinflammatory cytokines. Also, neutrophil serine proteases (NSPs) are capable of activating cytokines and recent studies reported that these proteases also contribute to NAFLD. These studies provided, for the first time, evidence that this inflammasome-independent pathway is involved in NAFLD. In our opinion, these new insights open up new approaches for therapeutic intervention.

Keywords: inflammasome; inflammation; interleukin-1; neutrophil serine proteases; nonalcoholic fatty liver disease; obesity.

Figure 1. The role of the NLRP3 inflammasome in IL-1 family cytokine activation.

Activation of the NLRP3 inflammasome and IL-1 family cytokines is a two-step process. In the first step (1) a PAMP, such as LPS, binds to its receptor (TLR4 for LPS) and activates via the adaptor protein MyD88 the transcription factor NF-kB. Next, NF-kB will translocate to the nucleus and up regulates the transcription of genes encoding for the NLRP3 protein complex and the pro-inflammatory cytokines IL-1β and IL-18. In the second step (2), a DAMP signal leads to association of the NLRP3 complex and activation of the effector protein caspase-1. In turn, caspase-1 cleaves pro-IL-1β and pro-IL-18 thereby releasing their active forms. These cytokines will be excreted from the cells and promote local (and systemic) inflammation. LPS: lypopolysacharide; TLR4: toll-like receptor; MyD88: myeloid differentiation primary response 88; NF-kB: nuclear factor kB; DAMP: damage associated molecular pattern; ASC: apotosis like associated protein containing a CARD domain (component of the inflammasome); NLRP3: NOD like receptor associated protein 3; (pro)-IL-1β: (pro) interleukin-1β; (pro)- IL-18: (pro)- interleukin 18.

Figure 2. The role of neutrophil serine proteases in IL-1 family cytokine activation

NSPs are stored in the azurophilic granules of neutrophils. Upon neutrophil activation, neutrophil serine proteases will be released into the cytosol (1) where they can activate pro-inflammatory cytokines. They can also be released into the phagolysosome where they have antimicrobial effects (2) or outside the cell where they can bind to the membrane (3) and activate extracellular cytokines, form NETs (4) and migrate into the extracellular space and activate pro-inflammatory cytokines (5). In the extracellular matrix AAT can inhibit NSPs which leads to the inhibition of cytokine activation (5).