Background The immune system is thought to be one pathway via which an absence of social ties or contact with others (i.e., ‘social isolation’) is associated with poor health. Yet, little is known about the mechanisms or processes that underpin the link. Relationships between isolation and inflammation are shown to vary with the type of tie that is missing. However, research investigating these associations often fails to examine social spheres separately to enable identification of underlying processes. This study has two aims: firstly, to pinpoint which areas of the social sphere are associated with markers of inflammation and secondly to examine the mediating pathways.

Methods Seven distinct domains of isolation and C-reactive protein (CRP) and fibrinogen was fitted to data from Understanding Society, (n=10481) and was validated by replication in the English Longitudinal Study of Aging (ELSA) (n=4865) with CRP fibrinogen and white blood count (WBC) as outcomes. Pathway analysis with health behaviours (smoking, drinking, exercise, and nutritional intake) and psychosocial stressors as mediators was examined. All models were adjusted for socio-demographic characteristics and other health-related factors (e.g., BMI and medication use).

Results The presence of a spouse and participation in social or community groups were found to be inversely associated with levels of CRP, fibrinogen, and WBC. Health behaviours were found to fully mediate associations in these social spheres in Understanding Society (coef. ≥ -0.004, 95%CI’s -0.006 to -0.002, p’s< 0.001) and partially in ELSA (coef. ≥ -0.005, 95%CI’s -0.008 to -0.002, p’s< 0.035). No significant associations in other spheres of isolation, or pathways through stress-responses or psychosocial stressors were identified.

Discussion Health behaviours were found to mediate the relationship between isolation in some social spheres, but not all, suggests that the processes underlying links from isolation to inflammation differ with the type of relationship that is missing and that isolation in some social spheres is may not be associated with inflammation. The cross-sectional design of this research make reverse causation a possibility in this research. Presence of a spouse and social group participation only are associated with inflammation, and this is through adverse health behaviours. Limitations notwithstanding, the findings here have implications for future research and understanding how lockdown due to COVID-19 may impact health.