The Novel Role of Metabolism-Associated Molecular Patterns in Sepsis

Abstract

Sepsis, a life-threatening organ dysfunction, is not caused by direct damage of pathogens and their toxins but by the host's severe immune and metabolic dysfunction caused by the damage when the host confronts infection. Previous views focused on the damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs), including metabolic proinflammatory factors in sepsis. Recently, new concepts have been proposed to group free fatty acids (FFAs), glucose, advanced glycation end products (AGEs), cholesterol, mitochondrial DNA (mtDNA), oxidized phospholipids (OxPLs), ceramides, and uric acid into metabolism-associated molecular patterns (MAMPs). The concept of MAMPs will bring new guidance to the research and potential treatments of sepsis. Nowadays, sepsis is regarded as closely related to metabolic disorders, and MAMPs play an important role in the pathogenesis and development of sepsis. According to this view, we have explained MAMPs and their possible roles in the pathogenesis of sepsis. Next, we have further explained the specific functions of different types of MAMPs in the metabolic process and their interactional relationship with sepsis. Finally, the therapeutic prospects of MAMPs in sepsis have been summarized.

Keywords: AGEs; free fatty acids; glucose; metabolism-associated molecular patterns; sepsis.

Figure 1

The production and types of MAMPs and their role in sepsis. When the metabolic balance is broken, the metabolic disorders will lead to a decrease in repair ability of the body. Meanwhile, metabolic disorders can cause extensive cell damage in the body tissues. Cell damage leads to increased levels of endogenous danger signaling molecules, including FFAs, AGEs, glucose, cholesterol crystal, and mtDNA, which are closely related to metabolic disorders and are defined as MAMPs. MAMPs can be recognized by PRRs and activate proinflammatory signaling pathways to promote the release of proinflammatory mediators. In addition, pathogenic substances such as LPS can also be recognized by PRRs and further activate the proinflammatory signaling pathway to cause the formation and deterioration of sepsis. Sepsis further enhances catabolism and increases MAMPs’ levels in turn. With the development of SIRS, the inflammatory process becomes uncontrollable, and the organ function and coagulation function become abnormal. Finally, these disorders cause the formation of MODS. MAMPs, metabolism-associated molecular patterns; FFAs, free fatty acids; AGEs, advanced glycation end products; mtDNA, mitochondrial DNA; PRRs, pattern recognition receptors; SIRS, systemic inflammatory response syndrome; MODS, multiple organ dysfunction syndromes.

Figure 2

Relationship between HG and sepsis. Sepsis can stimulate the hypothalamus to increase the secretion and release of CRH. Meanwhile, CRH promotes the synthesis and release of ACTH from the pituitary gland, and ACTH in turn stimulates the adrenal cortex to secrete cortisol, which can lead to an increase in blood glucose. Sepsis can also stimulate macrophages to secrete large amounts of IL-6, TNF-α, and other proinflammatory mediators. These proinflammatory mediators can disrupt the signaling of the insulin transduction pathway, and it is a major cause of insulin resistance in the host. Insulin resistance can further exacerbate HG in turning. Glucose is recognized by TLRs in a variety of tissue cells and activates NLRP3 inflammasomes that can cleave pro-caspase-1 into activated caspase-1 to induce inflammation. Activated caspase-1 processes pro-IL-1β and pro-IL-18 to form mature IL-1β and IL-18, promoting the development of inflammation in sepsis. HG, high glucose; CRH, corticotropin-releasing hormone; ACTH, adrenocorticotropic hormone; IL, interleukin; TNF, tumor necrosis factor; TLRs, Toll-like receptors.