Role of MyD88 signaling in the imiquimod-induced mouse model of psoriasis: focus on innate myeloid cells

Abstract

Psoriasis is a chronic skin disease associated with deregulated activation of immune cells and keratinocytes. In this study, we used the imiquimod (IMQ)-induced mouse model of psoriasis to dissect better the contribution of hematopoietic and skin-resident stromal cells to psoriasis development. The comparison of disease development in mice carrying the hematopoietic cell-specific deletion of MyD88 ( mice) with mice carrying the total MyD88 deficiency ( mice), we show that the progression of skin and systemic inflammation, as well as of epidermal thickening, was completely dependent on MyD88 expression in hematopoietic cells. However, both mouse strains developed some degree of epidermal thickening during the initial stages of IMQ-induced psoriasis, even in the absence of hematopoietic cell activation and infiltration into the skin, suggesting a contribution of MyD88-independent mechanisms in skin-resident stromal cells. With the use of conditional knockout mouse strains lacking MyD88 in distinct lineages of myeloid cells ( and mice), we report that MyD88 signaling in monocytes and Mϕ, but not in neutrophils, plays an important role in disease propagation and exacerbation by modulating their ability to sustain γδ T cell effector functions via IL-1β and IL-23 production. Overall, these findings add new insights into the specific contribution of skin-resident stromal vs. hematopoietic cells to disease initiation and progression in the IMQ-induced mouse model of psoriasis and uncover a potential novel pathogenic role for monocytes/Mϕ to psoriasis development.

IL-36γ Is a Strong Inducer of IL-23 in Psoriatic Cells and Activates Angiogenesis

“…Psoriasis macrophages secreted significantly more IL-23 following IL-36γ stimulation than healthy macrophages. Our findings also complement findings from an imiquimod-induced mouse model of psoriasis which has shown to be dependent on MyD88 signalling in macrophages ( 57 ). Whilst macrophage derived IL-23 is thought to be crucial to the immunopathological development of psoriasis lesions, we are the first to report a viable cytokine agonist for this induction, in IL-36γ.…”

IL-38 has an anti-inflammatory action in psoriasis and its expression correlates with disease severity and therapeutic response to anti-IL-17A treatment

“…This discrepancy can be explained considering that we use a full-length IL-38, whereas IL-36Ra was employed in a more active, N-terminally cleaved, form 7 , 43 . As two N-terminally cleaved forms of IL-38 with an increased inhibitory activity have been identified in tumor cells 44 , we hypothesize that IL-38 is processed in our in vivo experimental system, likely owing to extracellular neutrophil proteases abundantly released in the IMQ-treated skin 31 , 45 , 46 . Finally, the absence of a dose–response effect of IL-38 (as well as of IL-36Ra) on in vitro expression of inflammatory mediators support the hypothesis of Dinarello et al that IL-38 and IL-36Ra do not behave as classic receptor antagonists 5 .…”

Systemic Inflammation and Cardiovascular Comorbidity in Psoriasis Patients: Causes and Consequences

“…Using a mouse model where the psoriatic phenotype is induced by topical application of the immunomodulator imiquimod, Costa et al demonstrated that induction of the phenotype depends exclusively on hematopoietic cells. Using conditional knockout mouse strains, the active contribution of monocytes and macrophages on disease propagation and exacerbation was shown ( 86 ). With regard to atherosclerosis, Tabas and Lichtman recently reviewed how macrophages can be programmed for functions on a spectrum from inflammatory and host defense to resolution and repair in atherosclerotic plaques ( 87 ).…”