Brain innate immune response via miRNA-TLR7 sensing in polymicrobial sepsis

Abstract

Sepsis-associated encephalopathy (SAE) occurs in sepsis survivors and is associated with breakdown of the blood–brain barrier (BBB), brain inflammation, and neurological dysfunction. We have previously identified a group of extracellular microRNAs (ex-miRNAs), such as miR-146a-5p, that were upregulated in the plasma of septic mice and human, and capable of inducing potent pro-inflammatory cytokines and complements. Here, we established a clinically relevant mouse model of SAE and investigated the role of extracellular miRNAs and their sensor Toll-like receptor 7 (TLR7) in brain inflammation and neurological dysfunction. We observed BBB disruption and a profound neuroinflammatory responses in the brain for up to 14 days post-sepsis; these included increased pro-inflammatory cytokines production, microglial expansion, and peripheral leukocyte accumulation in the CNS. In a battery of neurobehavioral tests, septic mice displayed impairment of motor coordination and neurological function. Sepsis significantly increased plasma RNA and miRNA levels for up to 7 days, such as miR-146a-5p. Exogenously added miR-146a-5p induces innate immune responses in both cultured microglia/astrocytes and the intact brain via a TLR7-dependent manner. Moreover, mice genetically deficient of miR-146a showed reduced accumulation of monocytes and neutrophils in the brain compared to WT after sepsis. Finally, ablation of TLR7 in the TLR7 −/− mice preserved BBB integrity, reduced microglial expansion and leukocyte accumulation, and attenuated GSK3β signaling in the brain, but did not improve neurobehavioral recovery following sepsis. Taken together, these data establish an important role of extracellular miRNA and TLR7 sensing in sepsis-induced brain inflammation.

ExRNA Takes a Toll in Sepsis-associated Lung Injury

“…The finding that exRNA sensing by TLR7 resulted in organ injury has also been reported in other models ( 10 , 11 ), including a model of liver injury-induced lung inflammation by miR122 and sepsis-induced brain injury by miR146a-5p, suggesting that TLR7 senses multiple miRNAs and that the miRNA-TLR7 pathway is a potential target for lung and other remote organ injuries during sepsis and lung injury secondary to diverse insults. However, because differential cytokine and inflammatory responses are triggered in response to a diverse repertoire of exRNA and vesicles released during injury ( 12 ), the identity and functions of these different vesicular components, including exRNA, will need further investigation.…”

Expression of MicroRNAs in Sepsis-Related Organ Dysfunction: A Systematic Review

“…Zou et al analyzed miR-146a knock-out mice, describing a significant increase in neutrophils and monocytes in the brains of septic WT mice compared to the knock-out group [ 26 ]. Cultured microglia and astrocytes treated with miR-146a mimic showed marked chemokine CXCL2 production in microglia and lower CXCL2 production in astrocytes.…”

Emerging Role of Extracellular Rna in Innate Immunity, Sepsis, and Trauma

“…Plasma ex-miRNAs are proposed as disease biomarkers because they are differentially expressed in septic versus nonseptic critically ill patients or healthy controls (61,83). The recent studies in KO mice also clearly demonstrate a mechanistic role of miR-146a and the ssRNA sensor TLR7 in sepsis-induced inflammation and various organ injury (26,44,64,65,88,89).…”

“…3B). Ex-miRNAs can act on recipient cells via TLR7/8 signaling in a paracrine/endocrine fashion and play a role in various pathological conditions (71), such as cancer inflammation and metastasis (72), central nervous system (CNS) neurodegeneration (73), nocifensive and inflammatory pain (74), and sepsis-induced inflammation and organ injury (26,64,65). Moreover, using a computer predictive algorithm and a series of single U → A mutations in the miR-146a-5p molecule, Wang and colleagues identify the essential role of the U 12 U 13 xxxU 17 motif for miR-146a-5p–mediated cellular cytokine responses (26).…”