Severe injury and infection are associated with autonomic dysfunction. The realization that a dysregulation in autonomic function may predispose a host to excessive inflammatory processes has renewed interest in understanding the role of central nervous system (CNS) in modulating systemic inflammatory processes. Assessment of heart rate variability (HRV) has been used to evaluate systemic abnormalities and as a predictor of the severity of illness. Dissecting the relevance of neuroimmunomodulation in controlling inflammatory processes requires an understanding of the multiscale interplay between CNS and the immune response. A vital enabler in that respect is the development of a systems-based approach that integrates data across multiple scales, and models the emerging host response as the outcome of interactions of critical modules. Thus, a multiscale model of human endotoxemia, as a prototype model of systemic inflammation in humans, is proposed that integrates processes across the host from the cellular to the systemic host response level. At the cellular level interacting components are associated with elementary signaling pathways that propagate extracellular signals to the transcriptional response level. Further, essential modules associated with the neuroendocrine immune crosstalk are considered. Finally, at the systemic level, phenotypic expressions such as HRV are incorporated to assess systemic decomplexification indicative of the severity of the host response. Thus, the proposed work intends to associate acquired endocrine dysfunction with diminished HRV as a critical enabler for clarifying how cellular inflammatory processes and neural-based pathways mediate the links between patterns of autonomic control (HRV) and clinical outcomes.