Abstract
BackgroundStudies show that Toll-like receptors (TLRs), members of the innate immune system, might participate in the pathogenesis of the major depressive disorder (MDD). However, evidence of this participation in the brain of patients with MDD has been elusive.MethodsThis work explores whether the protein expression by immunodetection assays (Western blot) of elements of TLR-4 pathways controlling inflammation and the oxidative/nitrosative stress are altered in postmortem dorsolateral prefrontal cortex of subjects with MDD. The potential modulation induced by the antidepressant treatment on these parameters was also assessed. Thirty MDD subjects (15 antidepressant-free and 15 under antidepressant treatment) were matched for gender and age to 30 controls in a paired design.ResultsNo significant changes in TLR-4 expression were detected. An increased expression of the TLR-4 endogenous ligand Hsp70 (+ 33%), but not of Hsp60, and the activated forms of mitogen-activated protein kinases (MAPKs) p38 (+ 47%) and JNK (+ 56%) was observed in MDD. Concomitantly, MDD subjects present a 45% decreased expression of DUSP2 (a regulator of MAPKs) and reduced (− 21%) expression of the antioxidant nuclear factor Nrf2. Antidepressant treatment did not modify the changes detected in the group with MDD and actually increased (+ 25%) the expression of p11, a protein linked with the transport of neurotransmitters and depression.ConclusionData indicate an altered TLR-4 immune response in the brain of subjects with MDD. Additional research focused on the mechanisms contributing to the antidepressant-induced TLR-4 pathway modulation is warranted and could help to develop new treatment strategies for MDD.
Highlights
Studies show that Toll-like receptors (TLRs), members of the innate immune system, might participate in the pathogenesis of the major depressive disorder (MDD)
TLRs are expressed in immune cells, and in neurones, astroglia, and resident microglia [12,13,14]. Their ubiquitous distribution suggests that TLRs play other roles in non-pathogen-associated central nervous system (CNS) diseases/injuries, presumably through recognizing endogenous molecules released from damaged tissues, known as damage-associated molecular patterns (DAMPs) [15]
Western blot analysis The expression levels of TLR-4, Hsp60, Hsp70, phosphoERK 1/2, phospho-Jun N-terminal kinases (JNK), phospho-p38, p38 α/β, Phosphoinositide 3-kinase (PI3K), Kelch-like ECH-associated protein 1 (Keap-1), and S100A10 (p11) in cytosolic extracts and the expression levels of Dual-specificity phosphatases (DUSPs)-2, Nrf-2, and p65 (NF-κB subunit) in nuclear extracts from brain samples were analyzed through Western blot
Summary
Studies show that Toll-like receptors (TLRs), members of the innate immune system, might participate in the pathogenesis of the major depressive disorder (MDD). Evidence of this participation in the brain of patients with MDD has been elusive. TLRs are expressed in immune cells, and in neurones, astroglia, and resident microglia [12,13,14] Their ubiquitous distribution suggests that TLRs play other roles in non-pathogen-associated CNS diseases/injuries, presumably through recognizing endogenous molecules released from damaged tissues, known as damage-associated molecular patterns (DAMPs) (e.g., heat shock protein Hsp, Hsp70) [15]
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