Abstract
Bullous Pemphigoid (BP) is a skin autoimmune blistering disease characterized by immune-mediated degradation of the dermo-epidermal junction and release of a large number of inflammatory cytokines. Interleukin-1β (IL-1β) is a pleiotropic pro-inflammatory cytokine associated with inflammasome activation and known to be pivotal in several auto-immune and auto-inflammatory diseases. We sought to clarify the presence of inflammasome-dependent IL-1β and to investigate its role in BP. Skin biopsy specimens (n = 13), serum (n = 60), blister fluid (n = 26), and primary inflammatory cells from patients with BP were used to investigate inflammasome activation and function. We here highlighted a differential occurrence of a functional in situ inflammasome in patients with BP, biologically distinguished by IL-1β and NLRP3 expression. Clinically, elevated IL-1β levels were associated with the presence of erythema and urticarial plaques reflecting the inflammatory phase preceding blister formation. We further identified IL-17 and IL-23 as important molecules favoring IL-1β expression in monocyte-derived macrophages from BP patients. Finally, we demonstrated the ability of IL-1β to stimulate the release of the matrix metalloproteinase-9 in those macrophages, reinforcing the role of IL-1β in the auto-amplification loop of the inflammatory response associated to BP. However, whether this inflammasome is an epiphenomenon associated with BP disease or constitutes an amplification inflammatory step in certain patients still need to be determined. In the context of a precision medicine approach, our findings allowed us to delineate a subgroup of patients with BP that showed similarities with auto-inflammatory diseases. Subsequently, this opens up alternative therapeutic strategies targeting IL-1β pathway in the aim to control the early, pre-blistering inflammatory phase. Ultimately, this could also help in reducing the detrimental effects associated with high doses of corticosteroids treatment.
Highlights
Bullous pemphigoid (BP) is the most common auto-immune blistering skin disease, clinically characterized by urticarial erythema with tense blisters, and immunologically distinguished by the presence of autoantibodies directed against two structural proteins of the dermal-epidermal junction (DEJ), BP180, and BP230
To investigate whether enhanced IL-1β concentrations were related to the NLRP3 inflammasome activation, we investigated whether the blister fluid (BF) itself could favor the expression of IL-1β in macrophages
We identified IL-17 and IL-23 as significant inflammatory mediators for inflammasome priming in Bullous Pemphigoid (BP) monocytederived macrophages
Summary
Bullous pemphigoid (BP) is the most common auto-immune blistering skin disease, clinically characterized by urticarial erythema with tense blisters, and immunologically distinguished by the presence of autoantibodies directed against two structural proteins of the dermal-epidermal junction (DEJ), BP180, and BP230. The “sterile” NLRP3 inflammasome has been increasingly involved in non-infectious inflammatory responses related to autoimmune diseases [7], leading to the production of bioactive IL-1β. In BP, we previously showed that elastase released in skin blisters induced BP180 fragmentation [13], and the presence of biological active peptide within the blister fluid (BF) [4]. Those latter peptides were chemoattractant for neutrophils and favored the release of elastase, creating an auto feedback loop [4]. Studies are still needed to define the molecular mechanisms leading to NLRP3 inflammasome activation and to the expression and activation of IL-1β, notably with respect to BP disease activity
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