The emerging role of ASC in dendritic cell metabolism during Chlamydia infection

Abstract

Chlamydia trachomatis is a bacterial agent that causes sexually transmitted infections worldwide. The regulatory functions of dendritic cells (DCs) play a major role in protective immunity against Chlamydia infections. Here, we investigated the role of ASC in DCs metabolism and the regulation of DCs activation and function during Chlamydia infection. Following Chlamydia stimulation, maturation and antigen presenting functions were impaired in ASC-/- DCs compared to wild type (WT) DCs, in addition, ASC deficiency induced a tolerant phenotype in Chlamydia stimulated DCs. Using real-time extracellular flux analysis, we showed that activation in Chlamydia stimulated WT DCs is associated with a metabolic change in which mitochondrial oxidative phosphorylation (OXPHOS) is inhibited and the cells become committed to utilizing glucose through aerobic glycolysis for differentiation and antigen presenting functions. However, in ASC-/- DCs Chlamydia-induced metabolic change was prevented and there was a significant effect on mitochondrial morphology. The mitochondria of Chlamydia stimulated ASC-/- DCs had disrupted cristae compared to the normal narrow pleomorphic cristae found in stimulated WT DCs. In conclusion, our results suggest that Chlamydia-mediated activation of DCs is associated with a metabolic transition in which OXPHOS is inhibited, thereby dedicating the DCs to aerobic glycolysis, while ASC deficiency disrupts DCs function by inhibiting the reprogramming of DCs metabolism within the mitochondria, from glycolysis to electron transport chain.

Chlamydia psittaci -Infected Dendritic Cells Communicate with NK Cells via Exosomes To Activate Antibacterial Immunity

“…Russell et al suggest that the redirection of host ATP for Chlamydia intracellular survival and metabolic activity depletes energy available for exosome generation and release (28). Hence, it is possible that the augmented release of dexosomes is also due to metabolic reprogramming of infected DCs (47,55). This could allow host cell survival and promote killing as well as xenophagic elimination of Chlamydia.…”

Metabolic Control of Dendritic Cell Functions: Digesting Information

“…An early elevation of glycolysis is a metabolic hallmark of activated DCs and occurs in different mouse DC cultures, human moDCs in vitro , and mouse/human DC subsets in vivo / ex vivo (Figures 3, 4) shortly after pattern recognition receptor (PRR) stimulation with a wide range of pure pathogen-associated molecular patterns (PAMPs) or complex stimuli, such as lipopolysaccharides (LPSs) (13, 47–51), CpG oligodeoxynucleotides (13, 49), poly(I:C) (15, 49), R848/Resiquimod (49, 52), protamine–RNA complexes (pRNA) (53), zymosan (50), Pam 3 CSK 4 /Pam 2 CSK 4 (49), Aspergillus fumigatus (54), Chlamydia (55), heat-killed Propionibacterium acnes (13), and influenza A virus or rhinovirus infection (52). Interestingly, stimulants such as LPS and zymosan strongly induce upregulation of costimulatory molecules and cytokines, whereas weak activators such as house dust mite (HDM) or zymosan lacking TLR ligands (ZymD) provoke a milder GM-DC maturation profile (56).…”

Programmed Necrosis and Disease:We interrupt your regular programming to bring you necroinflammation

“…Bacterial and viral infections [142] NLRC4 Bacterial, fungal infection [143][144][145] IFI16 Viral infection [146] Pyrin Bacterial infection [147] ASC EC, bacterial, viral, parasitic and chlamydia infections [139,141,[148][149][150] Caspase-1 EC, bacterial, fungal, viral and parasitic infections [139,149,151] Caspase-4/5/11 Bacterial and parasitic infection [141,151,152] Ferroptosis GPX4 Neuron degeneration, acute kidney injury [126,127,130] Cystathioneγ-lyse Huntington's disease [129] Ferritin H Renal ischemia [153] Hepcidin Acute kidney injury [154] NETosis MPO Candida infection [131] DNase1 SLE, DM [136,155] Ferroptosis Hepcidin Ischemic brain [24,128] Heme oxygenase1 Acute kidney injury [180] NE RA, DM, atherosclerosis [67,156,181] development of a variety of chronic inflammatory and autoimmune diseases via different mechanisms ( Table 2). Necroptosis is triggered by a vast number of pathogens that express TLR3/4 ligands, resulting in the rupture of infected cells and the suppression of microbial growth [98].…”