TABLE 1.

Damage-associated molecular patterns (DAMPs), their receptors and molecular action in insulin resistance and Alzheimer’s disease.

DAMP	Receptors or sensors	Molecular action and effects	References
High mobility group box 1 (HMGB1) (alarmin)	RAGE, TLR4	Signal to the NF-κB signaling pathway and thus contributes to the inflammatory responses in type 2 diabetes mellitus, in the genesis and pathophysiology of IR and neurodegeneration.	Gonelevue et al., 2018; Paudel et al., 2020
Aβ (amyloid)	TLR4, TLR2, NLRP3, CD36, CD14 receptor	Aβ activates the NLRP1 and NLRP3 inflammasomes. The oligomers can disturb the functions of K+ channels, decreasing the intracellular K+ concentration and thus activating caspase-1. Increasing K+ efflux with valinomycin led to activated caspase-1 and IL-1β secretion from neurons. Aβ can also activate microglial cells in the brain through interaction with the surface receptor CD36, which induces the formation of a TLR2–TLR6 heterodimer and subsequently leads to NF-κB signaling.	Stewart et al., 2010; Heneka et al., 2018; Venegas and Heneka, 2019
Chromogranin A (CGA) (an acidic protein localized in secretory vesicles)	TLR4, CD14, or class A scavenger receptor	The stimulation of target receptors promotes the uptake of Aβ and phagolysosome formation. Upon lysosomal rupture, cathepsin B release is instrumental in the activation of procaspase-1 that ultimately produces IL-1β.	Lechner et al., 2004; Venegas and Heneka, 2019
ATP	P2 × 7R (an ATP-gated ion channel supporting Na+ and Ca2+ influx into and K+ efflux out of the cell)	The decrease in intracellular K+ leads to P2 × 7R-mediated NLRP3 inflammasome formation. Together with IL-1β release, NLRP3 inflammasome activation in the brain through the P2 × 7 receptor induces an increase of tau secretion in exosomes and its subsequent transmission to neurons.	Muñoz-Planillo et al., 2013; Asai et al., 2015; Venegas and Heneka, 2019
Ceramide (a sphingosine-based, lipid- signaling molecule that is formed from serine and 2 fatty acids)	NLRP3	Ceramide can act as an endogenous signal to caspase-1 cleavage and IL-1β secretion	Shin et al., 2015; Venegas and Heneka, 2019
S100	RAGE	Stimulate cell proliferation and migration and inhibit of apoptosis and differentiation, which participate in neurodegenerative processes. RAGE receptor activation leads to the activation the p38 MAPK cascade NF-κB.	Cristóvão and Gomes, 2019; Venegas and Heneka, 2019
mt-DNA and cf-DNA	TLR9 AIM2	Induce the release of interferon type 1 and TNF-α. Exogenous mtDNA fragments induced TLR9-mediated NF-κB activation in primary muscle cells. mtDNA increased TLR9 content in muscle cells. When cf-DNA binds to TLR, signaling occurs through MyD88, which leads to a type I IFN response. When cf-DNA binds to AIM2, caspase-1 is activated, and subsequently, IL-1β is released.	Shin et al., 2015; Venegas and Heneka, 2017; Yuzefovych et al., 2018
HSPs—heat shock proteins	PRRs (pattern recognition receptor). TLR2 and TLR4	Interaction with receptors leads to the induction of inflammatory cytokines such as TNF-α, IL-1β, IL-12, and GM-CSF.	Campanella et al., 2018; Venegas and Heneka, 2019
Homocysteine (Hcy)	NLRP3	Activation of the inflammasome with the subsequent release of interleukins. Hcy mediates the development of insulin resistance.	Smith et al., 2018; Zhang et al., 2018
Glucose	NLRP3	Induction of IL-1β secretion followed by increased apoptosis triggered by Fas via NF-κB and JNK and/or inhibiting insulin signaling.	Shin et al., 2015
IAPP [islet amyloid polypeptide (IAPP)–amylin]	NLRP3, CD36, and RAGE	IAPP has cytotoxic effects; assembly of the inflammasome leads to the formation of mature IL-1β.	Fawver et al., 2014; Shin et al., 2015
FFAs and their metabolites (palmitate)	NLRP3, TLR4	The production of inflammatory cytokines through activation of TLR and NLRP3 contributes to the development of insulin resistance by suppressing insulin signaling.	Shin et al., 2015