TY - JOUR
T1 - Toll-Like Receptor mRNA Levels in Schizophrenia
T2 - Association With Complement Factors and Cingulate Gyrus Cortical Thinning
AU - Weickert, Thomas W.
AU - Ji, Ellen
AU - Galletly, Cherrie
AU - Boerrigter, Danny
AU - Morishima, Yosuke
AU - Bruggemann, Jason
AU - Balzan, Ryan
AU - O'Donnell, Maryanne
AU - Liu, Dennis
AU - Lenroot, Rhoshel
AU - Weickert, Cynthia Shannon
AU - Kindler, Jochen
PY - 2024/3
Y1 - 2024/3
N2 - Background and Hypotheses: Previous studies revealed innate immune system activation in people with schizophrenia (SZ), potentially mediated by endogenous pathogen recognition receptors, notably Toll-like receptors (TLR). TLRs are activated by pathogenic molecules like bacterial lipopolysaccharides (TLR1 and TLR4), viral RNA (TLR3), or both (TLR8). Furthermore, the complement system, another key component of innate immunity, has previously been linked to SZ. Study Design: Peripheral mRNA levels of TLR1, TLR3, TLR4, and TLR8 were compared between SZ and healthy controls (HC). We investigated their relationship with immune activation through complement expression and cortical thickness of the cingulate gyrus, a region susceptible to immunological hits. TLR mRNA levels and peripheral complement receptor mRNA were extracted from 86 SZ and 77 HC white blood cells; structural MRI scans were conducted on a subset. Study Results: We found significantly higher TLR4 and TLR8 mRNA levels and lower TLR3 mRNA levels in SZ compared to HC. TLRs and complemental factors were significantly associated in SZ and HC, with the strongest deviations of TLR mRNA levels in the SZ subgroup having elevated complement expression. Cortical thickness of the cingulate gyrus was inversely associated with TLR8 mRNA levels in SZ, and with TLR4 and TLR8 levels in HC. Conclusions: The study underscores the role of innate immune activation in schizophrenia, indicating a coordinated immune response of TLRs and the complement system. Our results suggest there could be more bacterial influence (based on TLR 4 levels) as opposed to viral influence (based on TLR3 levels) in schizophrenia. Specific TLRs were associated with brain cortical thickness reductions of limbic brain structures.
AB - Background and Hypotheses: Previous studies revealed innate immune system activation in people with schizophrenia (SZ), potentially mediated by endogenous pathogen recognition receptors, notably Toll-like receptors (TLR). TLRs are activated by pathogenic molecules like bacterial lipopolysaccharides (TLR1 and TLR4), viral RNA (TLR3), or both (TLR8). Furthermore, the complement system, another key component of innate immunity, has previously been linked to SZ. Study Design: Peripheral mRNA levels of TLR1, TLR3, TLR4, and TLR8 were compared between SZ and healthy controls (HC). We investigated their relationship with immune activation through complement expression and cortical thickness of the cingulate gyrus, a region susceptible to immunological hits. TLR mRNA levels and peripheral complement receptor mRNA were extracted from 86 SZ and 77 HC white blood cells; structural MRI scans were conducted on a subset. Study Results: We found significantly higher TLR4 and TLR8 mRNA levels and lower TLR3 mRNA levels in SZ compared to HC. TLRs and complemental factors were significantly associated in SZ and HC, with the strongest deviations of TLR mRNA levels in the SZ subgroup having elevated complement expression. Cortical thickness of the cingulate gyrus was inversely associated with TLR8 mRNA levels in SZ, and with TLR4 and TLR8 levels in HC. Conclusions: The study underscores the role of innate immune activation in schizophrenia, indicating a coordinated immune response of TLRs and the complement system. Our results suggest there could be more bacterial influence (based on TLR 4 levels) as opposed to viral influence (based on TLR3 levels) in schizophrenia. Specific TLRs were associated with brain cortical thickness reductions of limbic brain structures.
KW - complement factors
KW - cortical thickness
KW - innate immunity
KW - magnetic resonance imaging
KW - schizophrenia
KW - toll like receptors
UR - http://www.scopus.com/inward/record.url?scp=85187202113&partnerID=8YFLogxK
UR - http://purl.org/au-research/grants/NHMRC/568807
U2 - 10.1093/schbul/sbad171
DO - 10.1093/schbul/sbad171
M3 - Article
C2 - 38102721
AN - SCOPUS:85187202113
SN - 0586-7614
VL - 50
SP - 403
EP - 417
JO - Schizophrenia Bulletin
JF - Schizophrenia Bulletin
IS - 2
ER -