Table 1 Pattern recognition receptors in the CNS and their contribution to neuroinflammatory diseases

TLRs

TLR2/TLR6

TLR2/TLR1

Astrocytes, microglia, oligodendrocytes, CECs

rexRNA as cofactor

IS: reduced infarct size in TLR2 KO mice [208, 481]; self rexRNA acts as cofactor of TLR2-ligands [112]

AD: TLR2 KO in a mouse model of AD aggravates AD pathology (Richard et al. 2008); upregulated TLR2 mRNA in amyloid plaques of patients [117]

MS: immune adjuvant properties of TLR2, TLR4, and TLR9 in murine EAE [101]

PD: TLR2-mediated signaling in a rat model of PD [279]; impaired TLR2 response in leukocytes of PD patients [63]

TLR3

Astrocytes, microglia, neurons, oligodendrocytes, CECs

mRNA

dsRNA

ssRNA

poly(I:C), siRNA

IS: inhibition of the TLR3/IRF3-IFNβ-signaling pathway reduced the inflammatory response in a rat model of transient global cerebral ischemia [62]; increased TLR3 and INFβ mRNA expression in PBMCs of stroke patients [78]

AD: increased TLR3 mRNA expression in brain tissue of AD patients [388]

MS: higher TLR3 expression in immune cells from MS patients [330]

PD: poly(I:C) injection in the substantia nigra from rats induced neuroinflammatory processes [76]

TLR4

Microglia, CECs, neurons

NETs

IS: neuroprotective effects of TLR4 KO in a murine model of transient focal cerebral ischemia [164]; NET formation in the rodent ischemic brain [416]

AD: TLR4 dependent upregulation of cytokines in a mouse model of AD [178]; upregulated TLR4 mRNA in amyloid plaques of patients [117]

MS: more severe symptoms in TLR4 and TLR9 KO mice subjected to EAE [255]; immune adjuvant properties of TLR2, TLR4, and TLR9 in EAE [101]

PD: TLR4-dependent SARS-CoV-2 infection and its possible role in PD pathogenesis [56]

TLR7/TLR8

Microglia, neurons

miRNA, ssRNA

IS: increased TLR7 and TLR8 expressions are associated with poor outcome and a greater inflammatory response in stroke patients [32]

AD: miRNAs can induce TLR7-dependent neurodegeneration [206]; upregulated TLR7 mRNA in amyloid plaques of patients [117]

MS: impaired TLR8 expression and signaling in PBMCs from MS patients [179]

PD: impaired TLR7/8 response in leukocytes from PD patients [63]; ssRNA-induced TLR7/MyD88-dependent neuronal cell death and neurodegeneration [207]

TLR9

Microglia, neurons

Oligodeoxynucleotides, unmethylated CpG DNA, DNA

IS: upregulation of TLR9 after cerebral ischemia reperfusion in mice [171]

AD: upregulated TLR9 mRNA in amyloid plaques of patients [117]; induction of TLR9 signaling by oligodeoxynucleotides ameliorates AD-related pathology [334]

MS: TLR9 and MyD88 are involved in the autoimmune process during EAE [307]; more severe EAE symptoms in TLR4 and TLR9 KO mice [255]; immune adjuvant properties of TLR2, TLR4, and TLR9 in rodent EAE [101]

PD: stimulation of the innate immune system by DNA oligodeoxynucleotides [334]

RAGE

Neurons, astrocytes, microglia, vascular cells

DNA, ssRNAs

IS: association of RAGE expression with acute ischemic stroke prognosis [225]

AD: targeting of RAGE and TLR4 in experimental models of AD has beneficial effects on the disease progression [294]

MS/PD: increased RAGE expressions in brains from MS, AD, and PD patients [353]; RAGE expression, NF-κB-induced cytokine production, and ROS generation are elevated in PD patients [175]

Cytosolic receptors

RIG-1, MDA-5, NLRs, cGAS, inflammasome

Neurons, astrocytes, microglia, vascular cells

dsDNA

IS: inhibition of cGAS ameliorates brain injury after ischemic stroke [215]; NLRP1/3 inflammasome proteins, IL-1β and IL-18 are elevated in brain tissue of mice underwent cerebral ischemia and stroke patients [103]

AD: expression of NLRPs, caspases, IL-1β and IL-18 is increased in PBMCs and Aβ plaques of AD patients [384]

MS: caspase-1 inhibition prevents inflammasome activation in models of MS [263]

PD: higher levels of IL-1β and caspase-1 in serum and brain tissue of PD patients [384]