Peripheral immune challenge can elicit microglia activation and depression-related symptoms. The balance of inflammatory signals in the
tryptophan pathway can skew the activity of indoleamine-
pyrrole 2,3
dioxygenase (IDO1) towards the metabolization of
tryptophan into
kynurenine (rather than
serotonin), and towards neuroprotective or neurotoxic metabolites. The
proteome changes that accompany
inflammation-associated depression-related behaviors are incompletely understood.
METHODS: The changes in microglia
protein abundance and post-translational modifications in wild type (WT) mice that exhibit depression-like symptoms after recovery from peripheral Bacille Calmette-Guerin (BCG) challenge were studied. This WT_BGG group was compared to mice that do not express depression-like symptoms after BCG challenge due to IDO1 deficiency by means of genetic knockout (BCG_KO group), and to WT Saline-treated (Sal) mice (WT_Sal group) using a mass spectrometry-based label-free approach.
RESULTS: The comparison of WT_BCG relative to WT_Sal and KO_BCG mice uncovered patterns of
protein abundance and acetylation among the
histone families that could influence microglia signaling and transcriptional rates. Members of the
histone clusters 1, 2 and 3 families were less abundant in WT_BCG relative to WT_Sal whereas members in the H2A family exhibited the opposite pattern. Irrespective of family, the majority of the
histones were less abundant in WT_BCG relative to KO_BCG microglia. Homeostatic mechanisms may temper the potentially toxic effects of high
histone levels after BCG challenge to levels lower than Sal.
Histone acetylation was highest in WT_BCG and the similar levels observed in WT_Sal and KO_BCG. This result suggest that
histone acetylation levels are similar between IDO1 deficient mice after immune challenge and unchallenged WT mice. The over-abundance of
tyrosine 3-monooxygenase/
tryptophan 5-monooxygenase activation
proteins (14-3-3 series) in WT_BCG relative to KO_BCG is particularly interesting because these
proteins activate another rate-limiting
enzyme in the
tryptophan pathway. The over-representation of
alcoholism and
systemic lupus erythematosus pathways among the
proteins exhibiting differential abundance between the groups suggest that these disorders share microglia activation pathways with BCG challenge. The over-representation of phagosome pathway among
proteins differentially abundant between WT_BCG and KO_BCG microglia suggest an association between IDO1 deficiency and phagocytosis. Likewise, the over-representation of the gap junction pathway among the differentially abundant
proteins between KO_BCG and WT_Sal suggest a multifactorial effect of BCG and IDO1 deficiency on cell communication.
CONCLUSIONS: The present study of
histone acetylation and differential
protein abundance furthers the understanding of the long lasting effects of peripheral immune challenges. Our findings offer insights into target
proteins and mechanisms that provide clues for
therapies to ameliorate
inflammation-associated depression-related behaviors.