👤 Suzanne Meldrum

Air pollution particles exacerbate allergic asthma and can enhance inflammatory responses to allergen exposure, but the cellular mechanisms involved remain incompletely defined. We examined how diesel exhaust particles (DEP) enhance house-dust-mite (HDM) inflammatory responses within the lung and characterised potential mechanisms that may contribute to enhanced type 2 (T2) inflammatory responses. In mice subjected to repeated intranasal exposures, DEP alone had modest effects, whereas DEP + HDM markedly increased type-2 inflammatory indicators (Serum IgE; Airway Il13, Il4 & Tslp) and eosinophilia alongside expansion of Th2 cells. Bulk transcriptomics showed far stronger differential expression in luminal airway cells than tissue, with a DEP + HDM-specific signature enriched for mast cells, alternatively activated macrophages (AAM), and B-cells in the lumen. Combined single-cell proteomic and transcriptomic profiling identified an expanded Cd11c⁺, SiglecF⁻, Apoe⁺, Gpnmb⁺ monocyte-derived macrophage subset (RM.Gp2), which showed increased type 2 chemokines Ccl8 and Ccl24 with DEP + HDM compared to HDM alone. Trajectory analysis placed RM.Gp2 downstream of Ccr2⁺ monocyte derived population, and protein/mRNA data supported a Ccl2-Ccr2-dependent influx that enlarges the RM.Gp2 pool. High-content imaging confirmed increased RM.Mo and RM.Gp2 numbers and higher total luminal Ccl8/Ccl24. F4/80⁺ luminal airway macrophages isolated from DEP pre-treated mice, demonstrated enhanced upregulation of Ccl8 and Ccl24 mRNA in response to ex vivo Il-4/Il-13 treatment, compared to macrophages isolated from control mice. Examination of an additional particle type (CeO Our data suggests that pollutant particles such as DEP may contribute to enhanced HDM induced type 2 inflammation by expanding Ccr2-dependent monocyte-derived macrophages into the airway lumen and licensing a Th2-cytokine-responsive chemokine programme (Ccl8- Ccr8 to recruit Th2 cells; Ccl24-Ccr3 to recruit eosinophils). These findings identify luminal recruited macrophages as important targets in allergic inflammation within the lung, providing insight into potential mechanisms from which exposure and disease mitigation strategies may be developed. Show less

The enzymes encoded by fatty acid desaturases (FADS) genes determine the desaturation of long-chain polyunsaturated fatty acids (LCPUFA). We investigated if haplotype and single nucleotide polymorphisms (SNPs) in FADS gene cluster can influence LCPUFA status in infants who received either fish oil or placebo supplementation. Children enrolled in the Infant Fish Oil Supplementation Study (IFOS) were randomly allocated to receive either fish oil or placebo from birth to 6 months of age. Blood was collected at 6 months of age for the measurement of fatty acids and for DNA extraction. A total of 276 participant DNA samples underwent genotyping, and 126 erythrocyte and 133 plasma fatty acid measurements were available for analysis. Twenty-two FADS SNPs were selected on the basis of literature and linkage disequilibrium patterns identified from the HapMap data. Haplotype construction was completed using PHASE. For participants allocated to the fish oil group who had two copies of the FADS1 haplotype consisting of SNP minor alleles, DHA levels were significantly higher compared to other haplotypes. This finding was not observed for the placebo group. Furthermore, for members of the fish oil group only, the minor homozygous carriers of all the FADS1 SNPs investigated had significantly higher DHA than other genotypes (rs174545, rs174546, rs174548, rs174553, rs174556, rs174537, rs174448, and rs174455). Overall results of this preliminary study suggest that supplementation with fish oil may only significantly increase DHA in minor allele carriers of FADS1 SNPs. Further research is required to confirm this novel finding. Show less