Identifying early inflammatory changes in monocyte-derived macrophages from a population with IQ-discrepant episodic memory.

BACKGROUND: Cells of the innate immune system including monocytes and macrophages are the first line of defence against infections and are critical regulators of the inflammatory response. These cells express toll-like receptors (TLRs), innate immune receptors which govern tailored inflammatory gene expression patterns. Monocytes, which produce pro-inflammatory mediators, are readily recruited to the central nervous system (CNS) in neurodegenerative diseases. METHODS: This study explored the expression of receptors (CD11b, TLR2 and TLR4) on circulating monocyte-derived macrophages (MDMs) and peripheral blood mononuclear cells (PBMCs) isolated from healthy elderly adults who we classified as either IQ memory-consistent (high-performing, HP) or IQ memory-discrepant (low-performing, LP). RESULTS: The expression of CD11b, TLR4 and TLR2 was increased in MDMs from the LP group when compared to HP cohort. MDMs from both groups responded robustly to treatment with the TLR4 activator, lipopolysaccharide (LPS), in terms of cytokine production. Significantly, MDMs from the LP group displayed hypersensitivity to LPS exposure. INTERPRETATION: Overall these findings define differential receptor expression and cytokine profiles that occur in MDMs derived from a cohort of IQ memory-discrepant individuals. These changes are indicative of inflammation and may be involved in the prodromal processes leading to the development of neurodegenerative disease

Demographic of subjects.

<p>Premorbid IQ was measured by the National Adult Reading Test (NART). Delayed verbal memory was determined by the Logical Memory subtest of the Wechsler Memory Scale.</p>*<p>HP <i>versus</i> LP; memory performance was less than 0.75 z-score below their estimated premorbid IQ.</p

Enhanced CD11b, TLR2 and TLR4 expression in MDMs from LPs.

<p>A) Plasma isolated from HP and LP groups displayed comparable levels of CRP. Data are presented as mean ± SEM and represent triplicate determinations from 35 and 12 samples per HP and LP groups, respectively. B) CD11b expression on PBMCs was unchanged between HP and LP subjects. C) Representative plots of CD11b⁺ cells in PBMC populations. Numbers beside gated areas indicate the percentage positive cells in that area. D) CD14 expression in MDMs was similar in LP and HP individuals following 7 days in culture. E) Percentage CD11b expression was increased in MDMs derived from the LP group, compared with the HP group (<i>P</i><0.05). F) Representative dot plots of CD11b⁺ cells in MDMs (with values beside gated areas indicating the percentage positive cells in that area) show marked differences between cohorts. G) CD11b mean fluorescence intensity on MDMs was increased in the LP group compared with the HP group (<i>P</i><0.05). H) CD11b mRNA in MDMs derived from the LP group was slightly, though not significantly, greater than values from the HP group (<i>P</i> = 0.19). I) TLR2 expression on CD11b⁺ PBMCs was similar in HP and LP groups and this is also shown in the representative dot plots of TLR2⁺ cells (J) which indicate the percentage positive cells. K) TLR2 expression on CD11b⁺ MDMs was increased in the LP group, compared to the HP group (<i>P</i> = 0.056) and this is also shown in the representative dot plots of TLR2⁺ cells (L) which indicate the percentage positive cells. M) TLR2 mRNA expression was increased on MDMs derived from the LP group compared with the HP group (<i>P</i><0.05). N) TLR4 expression on CD11b⁺ PBMCs was similar in HP and LP groups and this is also shown in the representative dot plots of TLR4⁺ cells (O) which indicate the percentage positive cells. P) TLR4 expression on CD11b⁺ MDMs was increased in the LP group compared with the HP group (<i>P</i><0.05) and this is also shown in the representative dot plots of TLR4⁺ cells (Q) which indicate the percentage positive cells. R) TLR4 mRNA expression on MDMs was increased in the LP group compared with the HP group (<i>P</i><0.05). Data are expressed as (B, E, I, K, N, P) mean percentage or fluoresence (G) expression ± SEM, or (D, H, M, R) mean relative expression ± SEM, of duplicate determinations in 35 and 12 samples per HP and LP groups, respectively.</p