Toll‐like receptor 4 differentially regulates adult hippocampal neurogenesis in an age‐ and sex‐dependent manner

Abstract

Toll‐like receptor 4 (TLR4) is primarily responsible for initiating an immune response following pathogen recognition. However, TLR4 is also expressed on neural progenitor cells and has been reported to regulate hippocampal neurogenesis as young male TLR4 knockout mice show increases in cell proliferation and doublecortin positive cells. Whether these effects occur in both sexes and are sustained with normal aging is currently unknown. The present study evaluated whether TLR4 deficiency alters adult hippocampal neurogenesis in young (3–4 months) and aged (18–20 months), male and female, TLR4 deficient (TLR4−/−; B6.B10ScN‐Tlr4lps‐del/JthJ) and wild type (WT) mice. Additionally, neurogenesis within the dorsal and the ventral hippocampal subdivisions was evaluated to determine if TLR4 has differential effects across the hippocampus. Bromodeoxyuridine (BrdU) was administered to quantify new cell survival as well as cell differentiation. Ki‐67 was measured to evaluate cell proliferation. Results show that young TLR4−/− females had higher rates of proliferation and neuronal differentiation in both the dorsal and ventral hippocampus relative to WT females. Young TLR4−/− males show elevated proliferation and neuronal differentiation mainly in the ventral hippocampus. While young TLR4−/− mice show enhanced neurogenesis compared to young WT mice, the increase was not apparent in the aged TLR4−/− mice. Both aged WT and TLR4−/− mice showed a decrease in proliferation, new cell survival, and neuronal differentiation compared to young WT and TLR4−/− mice. The data collectively indicate that TLR4 regulates hippocampal neurogenesis in young adults, but that these effects are region‐specific in males and that females show broader changes in neurogenesis throughout the hippocampus.

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“…However, at 28 days post BrdU injection, there was no significant difference in the number of proliferating cells between wild type and TLR-4 deficient mice, indicating that other signalling pathways may be responsible for survival of newly generated neurons. Similar findings have been affirmed in the hippocampus of adult TLR-4 -/mice, with enhanced NSPC proliferation, indicated by Ki67 labelling, and neuronal differentiation, demonstrated by number of NeuN + BrdU + cells, when compared to wild type mice [69]. An inhibitory role of TLR-4 was also verified in neurospheres grown from NSPCs derived from the human fetal brain, demonstrating reduced NSPC proliferation in the presence of TLR-4 antagonists [70].…”

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“…TLR2, TLR4, and TLR8 are also expressed in neural stem cells and play a role in adult hippocampal neurogenesis and learning and memory [ 120, 133, 134 ]. Interestingly, the role of TLR4 on adult hippocampal neurogenesis is sex dependent, where female mice deficient of TLR4 showed increased hippocampal neurogenesis [ 135 ]. In agreement with this finding, pharmacological inhibition of TLR4 via TLR4 antagonist (TAK-242) enhances memory in young female mice only [ 133 ].…”

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“…Using mainly genetic approaches (i.e., mice knockouts), several studies have started to unravel TLRs involvement in neuronal development, plasticity, and physiology, all processes that also depend on TLRs temporal and spatial expression in the brain [8][9][10][11][12]. TLR2 absence has a severe impact on brain function and structure: TLR2 knockout mice develop cognitive decline at ~7 months of age and show reduced regional cerebral blood flow, inhibited long-term potentiation, and increased blood-brain barrier permeability at 12 months [8].…”

“…TLR2 absence has a severe impact on brain function and structure: TLR2 knockout mice develop cognitive decline at ~7 months of age and show reduced regional cerebral blood flow, inhibited long-term potentiation, and increased blood-brain barrier permeability at 12 months [8]. In NPCs, TLR2 activation promotes hippocampal neurogenesis, whereas TLR3 and TLR4 signaling negatively regulates neuronal proliferation and differentiation [1,9]. Interestingly, recent findings showed sexually dimorphic and region-specific effects of TLR4 on hippocampal neurogenesis, and TLR4 signaling mainly affects neuronal proliferation in the brain of young adult females [9,10].…”

“…In NPCs, TLR2 activation promotes hippocampal neurogenesis, whereas TLR3 and TLR4 signaling negatively regulates neuronal proliferation and differentiation [1,9]. Interestingly, recent findings showed sexually dimorphic and region-specific effects of TLR4 on hippocampal neurogenesis, and TLR4 signaling mainly affects neuronal proliferation in the brain of young adult females [9,10]. TLR5 was found to promote neural differentiation both during brain development and in the adult brain, via NF-κB and interleukin-6/CREB pathways and the c-Jun N-terminal kinase (JNK) pathway, respectively [12].…”