TY - JOUR
T1 - Toll-like receptor 2 (TLR2)-deficiency impairs male mouse recovery from a depression-like state
AU - Medina-Rodriguez, Eva M.
AU - Cheng, Yuyan
AU - Michalek, Suzanne M.
AU - Beurel, Eléonore
AU - Jope, Richard S.
N1 - Funding Information:
This research was supported by a Merit Award from the Veterans Administration (BX003678) and grants from the NIMH (MH104656, MH110415).
Funding Information:
This research was supported by a Merit Award from the Veterans Administration (BX003678) and grants from the NIMH ( MH104656 , MH110415 ).
Publisher Copyright:
© 2020
PY - 2020/10
Y1 - 2020/10
N2 - Major depression is a prevalent, debilitating disease, yet therapeutic interventions for depression are frequently inadequate. Many clinical and pre-clinical studies have demonstrated that depression is associated with aberrant activation of the inflammatory system, raising the possibility that reducing inflammation may provide antidepressant effects. Using the learned helplessness mouse model, we tested if susceptibility or recovery were affected by deficiency in either of two receptors that initiate inflammatory signaling, Toll-like receptor-4 (TLR4) and TLR2, using knockout male mice. TLR4-/- mice displayed a strong resistance to learned helplessness, confirming that blocking inflammatory signaling through TLR4 provides robust protection against this depression-like behavior. Surprisingly, TLR2-/- mice displayed increased susceptibility to learned helplessness, indicating that TLR2-mediated signaling counteracts susceptibility. TLR2-mediated signaling also promotes recovery, as TLR2-/- mice demonstrated a severe impairment in recovery from learned helplessness. That TLR2 actually protects from learned helplessness was further verified by the finding that administration of the TLR2 agonist Pam3CSK4 reduced susceptibility to learned helplessness. Treatment with Pam3CSK4 also reversed chronic restraint stress-induced impaired sociability and impaired learning in the novel object recognition paradigm, demonstrating that TLR2 stimulation can protect from multiple impairments caused by stress. In summary, these results demonstrate that TLR2-mediated signaling provides a counter-signal to oppose deleterious effects of stress that may be related to depression, and indicate that TLR2 and TLR4 act oppositely to balance mood-relevant responses to stress.
AB - Major depression is a prevalent, debilitating disease, yet therapeutic interventions for depression are frequently inadequate. Many clinical and pre-clinical studies have demonstrated that depression is associated with aberrant activation of the inflammatory system, raising the possibility that reducing inflammation may provide antidepressant effects. Using the learned helplessness mouse model, we tested if susceptibility or recovery were affected by deficiency in either of two receptors that initiate inflammatory signaling, Toll-like receptor-4 (TLR4) and TLR2, using knockout male mice. TLR4-/- mice displayed a strong resistance to learned helplessness, confirming that blocking inflammatory signaling through TLR4 provides robust protection against this depression-like behavior. Surprisingly, TLR2-/- mice displayed increased susceptibility to learned helplessness, indicating that TLR2-mediated signaling counteracts susceptibility. TLR2-mediated signaling also promotes recovery, as TLR2-/- mice demonstrated a severe impairment in recovery from learned helplessness. That TLR2 actually protects from learned helplessness was further verified by the finding that administration of the TLR2 agonist Pam3CSK4 reduced susceptibility to learned helplessness. Treatment with Pam3CSK4 also reversed chronic restraint stress-induced impaired sociability and impaired learning in the novel object recognition paradigm, demonstrating that TLR2 stimulation can protect from multiple impairments caused by stress. In summary, these results demonstrate that TLR2-mediated signaling provides a counter-signal to oppose deleterious effects of stress that may be related to depression, and indicate that TLR2 and TLR4 act oppositely to balance mood-relevant responses to stress.
KW - Depression
KW - Inflammation
KW - Pam3CSK4
KW - Toll-like receptor-2
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U2 - 10.1016/j.bbi.2020.05.068
DO - 10.1016/j.bbi.2020.05.068
M3 - Article
C2 - 32479995
AN - SCOPUS:85085922551
VL - 89
SP - 51
EP - 58
JO - Brain, Behavior, and Immunity
JF - Brain, Behavior, and Immunity
SN - 0889-1591
ER -