Keratinization vs. Inflammation in Hidradenitis Suppurativa: Chicken Vs. Egg
Hidradenitis Suppuritiva is a vicious cycle of innate immunity,adaptive immunity, infection and enviromental factors such as smoking. Can we interrupt it?
Hidradenitis Suppurativa (HS) is a challenging, chronic inflammatory skin disease characterized by painful nodules, abscesses, and scarring in areas rich in hair follicles. Despite significant research, the precise mechanisms driving HS remain elusive, particularly the sequence of events that initiates the condition. A central debate persists: does aberrant keratinization of the hair follicle lead to inflammation, or does inflammation drive the follicular changes?
The Traditional View: Keratinization as the Initial Step
The widely accepted model suggests that hair shafts (HS) begin with the occlusion of the terminal hair follicle. This is thought to involve abnormal keratinization within the follicular epithelium, leading to blockage, dilation, and eventual rupture of the follicle. The release of follicular contents into the surrounding tissue then triggers a robust inflammatory response, characterized by the painful lesions seen in HS.
The Emerging View: Inflammation as the Primum Movens
An alternative perspective, supported by the concept of HS as an "autoinflammatory keratinization disease" (AiKD), suggests a different sequence. This paradigm proposes that underlying inflammation is the primum movens (primary driver), causing secondary alterations in follicular keratinization and structure. Genetic mutations linked to autoinflammatory pathways, such as those in IL36RN, are associated with AiKDs, including HS, lending support to this view. However, the sources note that whether infundibular alteration or immune cell infiltration is the primary cause has not been definitively defined.
Inflammation Plays a Key Role in All Stages
Regardless of the initial trigger, inflammation is a crucial component throughout the pathogenesis of HS. HS lesions exhibit elevated levels of pro-inflammatory cytokines like TNF-α, IL-1β, IL-17, and IL-23. The IL-1 pathway, in particular, is hyperactive. Both innate and adaptive immune cells contribute to this complex inflammatory cascade, and keratinocytes also play a role in releasing pro-inflammatory molecules.
Why Does This Matter?
Understanding whether keratinization or inflammation is the primary driver is vital for developing effective, targeted therapies. This might mean interrupting the initial keratinization step with targeted treatments. Current biological treatments often target key inflammatory pathways, such as TNF-α and IL-17, yet this is insufficient for achieving the desired clinical benefit. The "chicken or the egg" question in HS pathogenesis highlights the complexity of this debilitating condition. It remains an active area of research, with its resolution holding the key to more effective treatment strategies.
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