Abstract
Canadian Indigenous peoples (First Nations and Inuit) exhibit a high burden of infectious diseases including tuberculosis influenced by societal factors, and biological determinants. Toll-like receptor (TLR)-mediated innate immune responses are the first line of defence against infections. We examined the production of a panel of 30 cytokines in peripheral blood-derived mononuclear cells (PBMC) isolated from Indigenous and non-Indigenous participants, following stimulation with five different TLR ligands. The levels of TLR-induced pro-inflammatory cytokines such as IL-12/23p40, IL-16, and IFN-γ, and chemokines (MCP-4, MDC and eotaxin) were different between Indigenous compared to non-Indigenous participants. Antimicrobial cationic host defence peptides (CHDP) induced by TLR activation are critical for resolution of infections and modulate the TLR-to-NFκB pathway to alter downstream cytokine responses. Therefore, we examined the expression of human CHDP defensins and cathelicidin in PBMC. mRNA expression of genes encoding for def-A1 and def-B1 were significantly higher following stimulation with TLR ligands in Indigenous compared to non-Indigenous participants. The purinergic receptor P2X7 known to be activated by ATP released following TLR stimulation, is a receptor for CHDP. Therefore, we further examined single nucleotide polymorphisms (SNP) in P2X7. Indigenous participants had a significantly higher percentage of a P2X7 SNP which is associated with reduced function and lower ability to clear infections. These results suggest that a higher frequency of non-functional P2X7 receptors may influence the activity of downstream immune mediators required for resolution of infections such as pro-inflammatory cytokines and CHDP defensins, thus contributing to higher burden of infections in Indigenous population.
Highlights
The Canadian First Nations and Inuit groups experience a higher burden of infectious and chronic diseases compared to non-indigenous populations
We monitored the production of pro-inflammatory cytokines (TNFα and IL-1β) and that of the neutrophil chemokine IL-8, following stimulation of peripheral blood-derived mononuclear cells (PBMC) isolated from study participants with various TLR ligand (TLRL)
To elucidate a more comprehensive effect of Toll-like receptors (TLR)-mediated cytokine production, we examined the production of a panel of 30 different cytokines and chemokines using a multiplex MesoScale Discovery platform, in the tissue culture (TC) supernatants obtained following stimulation of PBMC with different TLRL, and compared these responses between the three groups
Summary
The Canadian First Nations and Inuit groups experience a higher burden of infectious and chronic diseases compared to non-indigenous populations. We have previously shown that the expression of TLR1/2-mediated immune response elements induced in the presence of a Mycobacterium tuberculosis (MTB)-related lipoprotein in macrophages are differentially regulated in a Canadian First Nation (Dene) population, compared to a Canadian non-Indigenous cohort[11] This included the expression of specific cytokines and a human CHDP cathelicidin LL-37. We hypothesized that TLR-mediated innate immune responses such as specific cytokine and CHDP expression required for antimicrobial functions may be differentially expressed within the Canadian Dene and Inuit populations, which may be a contributing factor for consequent high burden of infections. Results from this study suggest that SNP in P2X7 receptor, along with differential expression of TLR-mediated responses such as defensins, which play a critical role in antimicrobial functions, may contribute to higher burden of infections in Dene and Inuit peoples
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