Table 1.

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

Pattern recognition receptors		Cellular sources of expression	Endogenous/artificial RNA/DNA ligands	Associated pathologies
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]

Aβ: amyloid-β; AD: Alzheimer's disease; CECs: cerebral endothelial cells; cGAS: cyclic GMP/AMP (cGAMP) synthase; EAE: experimental autoimmune encephalomyelitis; IFN: interferon; IS: ischemic stroke; MDA5: melanoma differentiation-associated protein 5; MS: multiple sclerosis; NET: neutrophil extracellular trap; NLR: nucleotide-binding oligomerization domain (NOD)-like receptor; PBMC: peripheral blood mononuclear cell; PD: Parkinson's disease; poly(I:C): polyinosinic:polycytidylic acid; RAGE: receptor for advanced glycation end-products; RIG: retinoic acid-inducible gene; TLR: toll-like receptor