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

Abstract

The past two decades have witnessed a steady shift in our understanding of chronic inflammatorydisease - from linear cascades to regulated circuits, complete with feedback, amplification, and sus-ceptibility to runaway behaviour. Systems biologists have long emphasised that biological signallingnetworks are not mere cascades but dynamical systems, governed by gain, damping, and stabilityboundaries [55–57]. Neuroimmunology, too, has moved towards a reciprocal framing, recognisingthat neural and immune compartments engage in bidirectional signalling of considerable sophistica-tion. 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. Rosaceais uniquely suited to this purpose: its neurogenic cascade is compact, accessible, and mechanisticallytractable, yet it exhibits the full dynamical behaviour of a destabilised system. Patients flush in re-sponse to stimuli that ought to be subthreshold; they experience burning and stinging that persistlong after the inciting event; and they often fail to respond to therapies that target downstream in-flammatory mediators [11–13]. These clinical hallmarks, when viewed through a control-theoreticlens, are precisely what one would expect from a positive-feedback loop whose transcriptional gainhas exceeded its stability boundary. The paper formalises the neurogenic cascade as a two-dimensional feedback system withstate variables (neuronal excitability 𝑥(𝑡) and neuropeptide output 𝑦(𝑡)), a feedback branch(PAR-2-mediated sensitisation), and a transcriptional amplifier (CREB). A stability condition isderived from linearisation around the steady state: the loop remains stable when 𝐺 ⋅ 𝑆 < 𝛽𝑥𝛽𝑦 indimensional form, which after nondimensionalisation becomes 𝐺 ⋅ 𝑆 − 𝛽 < 1; beyond this threshold,the system becomes self-sustaining. This framing, we argue, is not metaphorical but follows directlyfrom 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 inmigraine, 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 thedermatologic exemplar of a broader class of “rogue loops” in medicine: systems in which transcrip-tional amplification drives pathological persistence. The article concludes by proposing a generaltemplate for identifying neuroimmune feedback diseases, outlining empirical strategies for valida-tion, and suggesting therapeutic implications - particularly the stabilisation of loop gain rather thanthe suppression of downstream mediators.The control-theoretic framework developed here provides the conceptual foundation for a com-panion therapeutic hypothesis [71], which proposes disulfiram-zinc as a gain-reducing interventiontargeting CREB. That paper, titled “Disulfiram and Zinc in Neurogenic Rosacea: A Mechanistic Hy-pothesis Targeting CREB-Mediated Transcriptional Amplification,” presents the translational casefor CREB inhibition as a stabilising strategy. The present work provides the theoretical scaffolding.