IL-23/IL-17 Axis Activates IL-1β-Associated Inflammasome in Macrophages and Generates an Auto-Inflammatory Response in a Subgroup of Patients With Bullous Pemphigoid

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.

Possible roles of CXCL13/CXCR5 axis in the development of bullous pemphigoid

“…As previous reports have suggested, IL‐17 plays pivotal roles in the development of BP by targeting myeloid cells, such as macrophages 4,12,18,19 . Indeed, Le Jan et al 4 .…”

“…As previous reports have suggested, IL‐17 plays pivotal roles in the development of BP by targeting myeloid cells, such as macrophages 4,12,18,19 . Indeed, Le Jan et al 4 . reported that the IL‐23/IL‐17 axis activates inflammasomes in macrophages, leading to the release of IL‐1β, which induces autocrine stimulation of macrophages to produce MMP9 in BP patients.…”

“…T‐helper (Th)17 cells have been characterized as a subset of CD4 + T cells that produce interleukin (IL)‐17A, IL‐17F and IL‐22, 1,2 which lead to the development of ectopic lymphoid follicles 3 . Th17 cells play significant roles in various cutaneous autoimmune diseases, such as bullous pemphigoid (BP), atopic dermatitis, and alopecia areata 4–7 . Moreover, IL‐17 induces the production of CXCL13 from lymphoid tissue organizer cells of mesenchymal origin 3 .…”

Osteoporosis in Skin Diseases

“…Moreover, Le Jan et al [93] identified IL-17 and related cytokines such as IL-22 and IL-23 in the serum and blister fluids of BP patients; these cytokines may lead to a feedback loop and the perpetuation of the autoinflammatory process increasing MMP-9 secretion and CXCL10 expression from leukocyte cells [94]. In line with this, sustained or enhanced serum levels of IL-17 were associated with relapses in BP [93]. Therefore, the marked association between OP and pemphigus can be explained at the molecular level by the immunopathogenic process and by the pro-inflammatory cells and cytokines shared in both disorders that lead to a net increase in bone resorption [92].…”

“…Pemphigus is an autoimmune disease dependent on T cells principally of self-reactive Th2 cells, which also involves pro-inflammatory cytokines of the innate immune system, such as TNF, IL-1, and IL-6 [92]. Moreover, Le Jan et al [93] identified IL-17 and related cytokines such as IL-22 and IL-23 in the serum and blister fluids of BP patients; these cytokines may lead to a feedback loop and the perpetuation of the autoinflammatory process increasing MMP-9 secretion and CXCL10 expression from leukocyte cells [94]. In line with this, sustained or enhanced serum levels of IL-17 were associated with relapses in BP [93].…”