IL-17+ Mast Cell/T Helper Cell Axis in the Early Stages of Acne

Abstract

Acne is a multifactorial disease driven by physiological changes occurring during puberty in the pilosebaceous unit (PSU) that leads to sebum overproduction and a dysbiosis involving notably Cutibacterium acnes. These changes in the PSU microenvironment lead to a shift from a homeostatic to an inflammatory state. Indeed, immunohistochemical analyses have revealed that inflammation and lymphocyte infiltration can be detected even in the infraclinical acneic stages, highlighting the importance of the early stages of the disease. In this study, we utilized a robust multi-pronged approach that included flow cytometry, confocal microscopy, and bioinformatics to comprehensively characterize the evolution of the infiltrating and resident immune cell populations in acneic lesions, beginning in the early stages of their development. Using a discovery cohort of 15 patients, we demonstrated that the composition of immune cell infiltrate is highly dynamic in nature, with the relative abundance of different cell types changing significantly as a function of clinical lesion stage. Within the stages examined, we identified a large population of CD69+ CD4+ T cells, several populations of activated antigen presenting cells, and activated mast cells producing IL-17. IL-17+ mast cells were preferentially located in CD4+ T cell rich areas and we showed that activated CD4+ T cells license mast cells to produce IL-17. Our study reveals that mast cells are the main IL-17 producers in the early stage of acne, underlying the importance of targeting the IL-17+ mast cell/T helper cell axis in therapeutic approaches.

Roles of Mast Cells in Cutaneous Diseases

“…Hyperkeratotic plugs composed of corneocytes in the lower portion of the follicular infundibulum create a new environment that impacts the microbiota and fosters proliferation of a gram-positive bacillus, Cutibacterium acnes . IL-17A-producing mast cells were detected in the perifollicular area of acne vulgaris lesions ( 23 ). Activated memory/effector CD4 + T cells induced IL-17A production by human mast cells, implying a contribution of mast cells to development of acne vulgaris ( 23 ).…”

“…IL-17A-producing mast cells were detected in the perifollicular area of acne vulgaris lesions ( 23 ). Activated memory/effector CD4 + T cells induced IL-17A production by human mast cells, implying a contribution of mast cells to development of acne vulgaris ( 23 ). However, their precise role remains unclear.…”

From IL-17 to IFN-γ in inflammatory skin disorders: Is transdifferentiation a potential treatment target?

“…Additionally, the IFN-γ-induced chemokines—CXCL9, CXCL10, and CXCL11—are overexpressed ( 42 ). The combined expression of CXCR3 and CD161 was present in 15% of conventional T cells, reminiscent of pathogenic Th17.1 lymphocytes ( 43 ). Cutibacterium acnes can trigger the concomitant production of IL-17 and IFN-γ ( 44 ).…”

Potential roles of gut microbial tryptophan metabolites in the complex pathogenesis of acne vulgaris

“…Specific anti- C. acnes activate complement and recruit neutrophils ( Dreno et al, 2015 ). CD4 + T cells were also found in patches of acne where they exacerbate inflammation ( Agak et al, 2014 ; Kelhälä et al, 2014 ; Kistowska et al, 2014 ; Eliasse et al, 2021 ). An exploration of roles and mechanisms of GM Trp metabolism in mediating innate immune inflammation and sebaceous gland function during acne vulgaris pathology follows ( Figure 1 ).…”

“…T lymphocytes have been demonstrated to appear first in early acne lesions ( Norris and Cunliffe, 1988 ; Jeremy et al, 2003 ) and IL-17-producing cells with increased IL-17A tissue expression have also been found in lesions ( Agak et al, 2014 ; Kistowska et al, 2014 ). Activation of mast cells to produce IL-17 in CD4 + T cell rich areas has been suggested, even in the subclinical stages of acne ( Eliasse et al, 2021 ), and scattered distribution of IL-17A positive cells was observed in both the papillary dermis and around sebaceous follicles in acne lesions ( Kelhälä et al, 2014 ).…”