Mental health modulates the risk of common chronic conditions like cardiovascular disease, cancer and diabetes. Although inflammation is thought to partly explain this link, its relation with mental health is still unclear and largely unexplored. We investigated three scales assessing psychological resilience (CD-RISC), depression symptoms (PHQ8) and mental wellbeing (SF36-MCS) in an Italian adult population cohort (Nmax=16,952). We performed stepwise generalized linear models to test the

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... ation between each scale and INFLA-score, a composite blood-based inflammation index. At each step, a class of potential mediators was included in the model, namely health conditions, lifestyle factors, or both (full model). Full model analysis was also conducted on single blood markers involved in the inflammatory process. In the baseline model, we observed significant associations of PHQ8 (standardized β=0.024, p=8.9x10-3) and SF36-MCS (β=-0.021, p=7x10-3) with INFLA-score. These associations survived adjustment for health conditions but not for lifestyle factors, which explained 81% and 17% of the association with PHQ8 and SF36-MCS, respectively. Significant associations (p<4.2x10-3) after mediator adjustment were observed for single low-grade inflammation markers, including platelet distribution width (with PHQ8 and CD-RISC), granulocyte- and neutrophil-to-lymphocyte ratios, monocyte and lymphocyte fractions (with SF36-MCS). These findings suggest that the relationship between mental health and low-grade inflammation is largely influenced by lifestyle. However, the associations with specific biomarkers related to inflammation are partly independent and might be explained by biological factors. Interestingly, these associations are in line with recent blood transcriptomic analyses of depressed subjects, reporting up- and down-regulation of genes related to innate and adaptive immunity, respectively.