IL-17-Dependent Dysregulated Cutaneous Immune Homeostasis in the Absence of the Wiskott-Aldrich Syndrome Protein.

Katherine E Herman,Angela Hughson,Lisa A Beck,Steven R Gill,Takeshi Yoshida,Alex Grier,Deborah J Fowell

doi:10.3389/fimmu.2022.817427

Katherine E Herman, Angela Hughson + Show 5 more

Open Access

https://doi.org/10.3389/fimmu.2022.817427

Copy DOI

Abstract

Wiskott–Aldrich Syndrome (WAS) is characterized by recurrent infections, thrombocytopenia, and eczema. Here, we show that WASp-deficient mice on a BALB/c background have dysregulated cutaneous immune homeostasis with increased leukocyte accumulation in the skin, 1 week after birth. Increased cutaneous inflammation was associated with epithelial abnormalities, namely, altered keratinization, abnormal epidermal tight junctional morphology and increased trans-epidermal water loss; consistent with epidermal barrier dysfunction. Immune and physical barrier disruption was accompanied by progressive skin dysbiosis, highlighting the functional significance of the disrupted cutaneous homeostasis. Interestingly, the dysregulated immunity in the skin preceded the systemic elevation in IgE and lymphocytic infiltration of the colonic lamina propria associated with WASp deficiency. Mechanistically, the enhanced immune cell accumulation in the skin was lymphocyte dependent. Elevated levels of both Type 2 (IL-4, IL-5) and Type 17 (IL-17, IL-22, IL-23) cytokines were present in the skin, as well as the ‘itch’ factor IL-31. Unexpectedly, the canonical WAS-associated cytokine IL-4 did not play a role in the immune dysfunction. Instead, IL-17 was critical for skin immune infiltration and elevation of both Type 2 and Type 17 cytokines. Our findings reveal a previously unrecognized IL-17-dependent breakdown in immune homeostasis and cutaneous barrier integrity in the absence of WASp, targeting of which may provide new therapeutic possibilities for the treatment of skin pathologies in WAS patients.

Highlights

Among patients with primary immunodeficiency disorders (PIDD), 40–70% have cutaneous pathology [1,2,3,4]
We noted some variability between experiments in the overall magnitude of inflammation, but in all cases the difference between WT and Wiskott–Aldrich Syndrome (WAS)−/− mice was significant within each individual experiment (Figure 1B)
Cutaneous inflammation was only observed in the full absence of WASp, WAS+/− mice showing no overt skin inflammation (Figure 1D)

Summary

Introduction

Among patients with primary immunodeficiency disorders (PIDD), 40–70% have cutaneous pathology [1,2,3,4]. WAS eczema is unclear but the microbial complications are likely secondary to impaired anti-microbial immunity [8,9,10]. In contrast to a defective IFN-g response, patients with WAS deficiency develop robust type 2 responses, namely, elevated serum IgE, atopic-like eczema, and food allergy [11, 12]. In the absence of WASp, both innate and adaptive immunity is compromised with defects in phagocytosis, impaired CD8 T cell and NK cytotoxicity, reduced cytokine secretion, and altered migration [21, 22]. Defects in regulatory function (Tregs, Bregs and anti-inflammatory, IL-10-producing, macrophages) contribute to WAS pathologies resulting in unrestrained immune responses [11, 23,24,25,26,27,28]

Methods

Results

Conclusion