Does Infection-Induced Immune Activation Contribute to Dementia?
Tatiana Barichello1,2,*(), Jaqueline S. Generoso2, Jessica A. Goularte2, Allan Collodel2, Meagan R. Pitcher1, Lutiana R. Simões2, João Quevedo1,3, Felipe Dal-Pizzol4
1 Center for Translational Psychiatry, Department of Psychiatry and Behavioral Sciences, The University of Texas Medical School at Houston, Houston, TX, USA 2 Laboratório de Microbiologia Experimental, Programa de Pós-Graduação em Ciências da Saúde, Unidade Acadêmica de Ciências da Saúde, Universidade do Extremo Sul Catarinense, Criciúma, SC, Brazil. 3 Laboratório de Neurociências, Programa de Pós-Graduação em Ciências da Saúde, Unidade Acadêmica de Ciências da Saúde, Universidade do Extremo Sul Catarinense, Criciúma, SC, Brazil. 4 Laboratorio de Fisiopatologia Experimental, Programa de Pos-Graduacao em Ciencias da Saude, Unidade Academica de Ciencias da Saude, Universidade do Extremo Sul Catarinense, 88806-000 Criciuma, SC, Brazil.
The central nervous system (CNS) is protected by a complex blood-brain barrier system; however, a broad diversity of virus, bacteria, fungi, and protozoa can gain access and cause illness. As pathogens replicate, they release molecules that can be recognized by innate immune cells. These molecules are pathogen-associated molecular patterns (PAMP) and they are identified by pattern-recognition receptors (PRR) expressed on antigen-presenting cells. Examples of PRR include toll-like receptors (TLR), receptors for advanced glycation endproducts (RAGE), nucleotide binding oligomerisation domain (NOD)-like receptors (NLR), c-type lectin receptors (CLR), RIG-I-like receptors (RLR), and intra-cytosolic DNA sensors. The reciprocal action between PAMP and PRR triggers the release of inflammatory mediators that regulate the elimination of invasive pathogens. Damage-associated molecular patterns (DAMP) are endogenous constituents released from damaged cells that also have the ability to activate the innate immune response. An increase of RAGE expression levels on neurons, astrocytes, microglia, and endothelial cells could be responsible for the accumulation of αβ-amyloid in dementia and related to the chronic inflammatory state that is found in neurodegenerative disorders.
Figure 1. Recognition of pathogens by the innate immune system. Toll-like receptors (TLR) recognize molecular motifs that are expressed by pathogens or endogenous ligands released from damaged cells. AGE, advanced glycation end products; AP-1, activator protein-1; ASC, apoptosis-associated speck-like protein containing a caspase-recruitment domain; Cdc42, cell division control protein 42 homolog; Csp3, caspase-3; eNOS, endothelial nitric oxide synthase; ERK, extracellular signal regulated; IL, interleukin; IKK, NEMO/IKKα/IKKß complex; IRAK-4, interleukin-1 receptor-associated kinase 4; IκB, inhibitor of NF-κB; IKK, IκB kinase; INF, interferon; IRF3, interferon regulatory factor 3; JNK, c-jun N-terminal kinase; MAPK, mitogen-activated protein kinases; MyD88, myeloid differentiation factor 88; MEK, mitogen-activated protein kinase; MKK, MAPK kinase; NADPH, Nicotinamide adenine dinucleotide phosphate; NEMO, NF-κB essential modulator, IKKγ; NF-κB, nuclear transcription factor kappa B; NLRP3, nucleotide-binding domain and leucine-rich repeat protein 3; NO, nitric oxide; NODs, nucleotide binding oligomerisation domains; PI3K, phosphatidylinositide 3-kinase; PKB, protein kinase A; RAGE; receptor for advanced glycation endproducts; PKR, protein kinase RNA-activated; ROS, reactive oxygen species; TAB, TGF-β-activated kinase 1-binding protein 1; TAK1, TGFß activated kinase 1; TIRAP, TIR-containing protein; TLRs, toll-like receptors; TRAF, receptor-associated factor; TRAM, TRIF-related adaptor molecule; TRIF, TIR-domain-containing adapter-inducing interferon-β
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