The intersectional psychoneuroendocrinology framework: Social and geographic patterning of systemic inflammation in...

Psychoneuroendocrinology has detailed how social conditions activate the sympathetic nervous system and dysregulate the hypothalamic-pituitary-adrenal axis, producing inflammatory burden. What remains less understood is the level at which those processes are organized. Intersectional structural position is proposed here as a central organizing level of neuroendocrine regulation, and selected downstream implications of that proposition are evaluated at population scale. The Intersectional Psychoneuroendocrinology framework specifies two pathways through which intersecting structural conditions organize neuroendocrine function. The first operates through threat appraisal, activating the sympathetic nervous system and driving proinflammatory transcriptional signaling. The second operates through residential and geographic conditions patterned by structural position, which may calibrate HPA function through sustained everyday conditions without consciously reported appraisal of a discrete threat. Chronic exposure through both pathways is proposed to sustain systemic inflammatory burden. In 14,601 adults from the All of Us Research Program, Multilevel Analysis of Individual Heterogeneity and Discriminatory Accuracy showed that high-sensitivity C-reactive protein was patterned across 27 intersectional positions defined by race and ethnicity, gender, and income. Between-position variation was 3.09 % before adjustment and 0.31 % after adjustment for the structural dimensions, age, body mass index, smoking, and education. Adding the main effects of the three structural dimensions accounted for 83.2 % of the covariate-adjusted between-position variance, and median hs-CRP varied 2.5-fold across positions. A cross-classified model showed additional patterning across broad geographic areas after accounting for structural position, individual covariates, and area deprivation. Systemic inflammatory burden showed modest but detectable patterning across jointly defined structural positions and broad geographic contexts. Most adjusted between-position variation followed an additive pattern, consistent with cumulative inequality across dimensions of structural power rather than large position-specific departures. Considered alongside evidence on chronic stress physiology, these findings provide an initial empirical evaluation of the framework's downstream propositions and identify the need for longitudinal, multimarker, and spatially explicit tests of its proposed pathways.