Destabilised Neuroimmune Feedback Loops: A Control-Theoretic Framework and Its Application to Rosacea

The past two decades have witnessed a steady shift in our understanding of chronic inflammatory disease—from linear cascades to regulated circuits, complete with feedback, amplification, and susceptibility to runaway behaviour. Systems biologists have long emphasised that biological signalling networks are not mere cascades but dynamical systems, governed by gain, damping, and stability boundaries [55–57]. Neuroimmunology, too, has moved towards a reciprocal framing, recognising that neural and immune compartments engage in bidirectional signalling of considerable sophistication. Yet dermatology has remained curiously insulated from this conceptual migration. The present work seeks to remedy this gap by proposing a general control-theoretic framework for destabilised neuroimmune feedback diseases—conditions in which transcriptional amplification drives pathological persistence. The framework is developed through the lens of one such condition: neurogenic rosacea. Rosacea is uniquely suited to this purpose: its neurogenic cascade is compact, accessible, and mechanistically tractable, yet it exhibits the full dynamical behaviour of a destabilised system. Patients flush in response to stimuli that ought to be subthreshold; they experience burning and stinging that persist long after the inciting event; and they often fail to respond to therapies that target downstream inflammatory mediators [11–13]. These clinical hallmarks, when viewed through a control-theoretic lens, are precisely what one would expect from a positive-feedback loop whose transcriptional gain has exceeded its stability boundary. The paper formalises the neurogenic cascade as a feedback system with a state variable (neuronal excitability), an output (Substance P release), a feedback branch (PAR-2-mediated sensitisation), and a transcriptional amplifier (CREB). A stability condition is derived: the loop remains stable when the product of CREB-dependent gain and feedback sensitivity is less than unity; beyond this threshold, the system becomes self-sustaining. This framing, we argue, is not metaphorical but follows directly from established signalling biology [14, 15]. The loop closes, and under certain parameter regimes, it runs away. The framework is then extended beyond rosacea. Analogous loop architectures are identified in migraine, chronic pain, asthma, and atopic dermatitis—conditions not traditionally grouped together, but which share a common dynamical signature [62–65]. Rosacea, in this context, becomes the dermatologic exemplar of a broader class of "rogue loops" in medicine: systems in which transcriptional amplification drives pathological persistence. The article concludes by proposing a general template for identifying neuroimmune feedback diseases, outlining empirical strategies for validation, and suggesting therapeutic implications—particularly the stabilisation of loop gain rather than the suppression of downstream mediators. The control-theoretic framework developed here provides the conceptual foundation for a companion therapeutic hypothesis [71], which proposes disulfiram-zinc as a gain-reducing intervention targeting CREB. That paper, titled "Disulfiram and Zinc in Neurogenic Rosacea: A Mechanistic Hypothesis Targeting CREB-Mediated Transcriptional Amplification," presents the translational case for CREB inhibition as a stabilising strategy. The present work provides the theoretical scaffolding.