Traveling wave of inflammatory response to regulate the expansion or shrinkage of skin erythema

Abstract

Many skin diseases show circular red lesions on the skin, called erythema. Erythema is characterized by the expansion of its circular area solely from local stimulation. A pathological inflammatory response caused by the stimulation persistently increases inflammatory mediators in the dermis, whereas a normal inflammatory response transiently increases mediators, resulting in the shrinkage of the erythema. Although the diffusion of mediators theoretically reproduces the expansion, how the inflammatory response expands or shrinks the erythema remains unknown. A possibility is positive feedback, which affects mediator production and can generate two distinct stable states (i.e., inflamed and noninflamed), referred to as bistability. Bistability causes a state transition either from the noninflamed to inflamed state or the reverse direction by suprathreshold stimulation. Additionally, the diffusion selectively causes state transition in either direction, resulting in spatial spread of the transited state, known as the traveling wave. Therefore, we hypothesize that the traveling wave of the inflammatory response can account for both the expansion and shrinkage. Using a reaction-diffusion model with bistability, we theoretically show a possible mechanism in which the circular inflamed area expands via the traveling wave from the noninflamed to the inflamed state. During the expansion, the boundary between the inflamed and noninflamed areas moves at a constant velocity while maintaining its concentration gradient. Moreover, when the positive feedback is weak, the traveling wave selectively occurs from the inflamed to noninflamed state, shrinking the inflamed area. Whether the inflamed area expands or shrinks is mainly controlled by the balance of mediator concentration between the noninflamed and inflamed states, relative to the threshold. The traveling wave of the inflammatory response provides an experimentally testable framework for erythema expansion and shrinkage, thereby contributing to the development of effective treatments, including probiotics.

Diffusive mediator feedbacks control the health-to-disease transition of skin inflammation

“…On the contrary, when S T was closer to the S H than the S I , the inflamed area shrank rather than fading ( S4A Fig ). These results are general outcomes of the traveling wave of bistable systems [ 36 ], and are consistent with the previous theoretical studies on inflammation [ 23 , 38 ].…”

“…Previous reaction-diffusion models, including chemotactic cells, have reproduced the resolution of inflammation in the lung [ 21 , 22 ]; however, the resolution of erythema has not received much attention. Although the overproduction of pro-inflammatory mediators is thought to cause expanding erythema in many modeling studies of these inflammatory skin diseases [ 15 – 20 , 23 ], the mechanism by which overproduction through the feedback selectively drives the transition from a healthy state with fading erythema to a disease state with each of the five types of expanding erythema remains unclear.…”

“…The area of microinflammation with a high concentration of pro-inflammatory mediators is considered as a "seed" region, and its projection to the surface is colored in red. https://doi.org/10.1371/journal.pcbi.1011693.g001 PLOS COMPUTATIONAL BIOLOGY these inflammatory skin diseases [15][16][17][18][19][20]23], the mechanism by which overproduction through the feedback selectively drives the transition from a healthy state with fading erythema to a disease state with each of the five types of expanding erythema remains unclear.…”

Disordered spatial pattern of redness signal on facial skin and visual perception of health, stress, and hidden aging

“… 14 , 15 Apart from severe cases, daily environmental stressors such as UV, dryness, and chemical and bacterial infection, trigger inflammation, resulting in temporary and chronic red signals by altering vascular permeability and inducing angiogenesis. 16 , 17 As mathematical models explain redness patterns caused by disordered vascular permeability and angiogenesis, 18 , 19 there are certain shape and spatial pattern of redness generated by acute and chronic inflammation; however, association between human perception and shape and spatial pattern of redness (a*) has not been well studied.…”

“…We hypothesized that skin with red signal localizing in uneven spatial pattern and shape is perceived more unhealthy because of some reasons, (1) increasing a* value evenly on entire facial skin enhanced healthy appearance 11 , (2) temporal inflammation is induced by secretion of inflammatory mediators result in temporal circular erythema, 18 and (3) semi‐chronic inflammation and cellular senescence followed by angiogenesis causes complex and uneven pattern of redness. 19 , 20 Therefore, two rating study are performed to examine this hypothesis.…”