Abstract
Cutaneous group 2 innate lymphoid cells (ILC2) are spatially and epigenetically poised to respond to barrier compromise and associated immunological threats. ILC2, lacking rearranged antigen-specific receptors, are primarily activated by damage-associated cytokines and respond with type 2 cytokine production. To investigate ILC2 potential for direct sensing of skin pathogens and allergens, we performed RNA sequencing of ILC2 derived from in vivo challenged human skin or blood. We detected expression of NOD2 and TLR2 by skin and blood ILC2. Stimulation of ILC2 with TLR2 agonist alone not only induced interleukin-5 (IL-5) and IL-13 expression but also elicited IL-6 expression in combination with Staphylococcus aureus muramyl dipeptide (MDP). Heat-killed skin-resident bacteria provoked an IL-6 profile in ILC2 in vitro that was notably impaired in ILC2 derived from patients with nucleotide-binding oligomerization domain-containing protein 2 (NOD2) mutations. In addition, we show that NOD2 signaling can stimulate autophagy in ILC2, which was also impaired in patients with NOD2 mutations. Here, we have identified a role for ILC2 NOD2 signaling in the differential regulation of ILC2-derived IL-6 and have reported a previously unrecognized pathway of direct ILC2 bacterial sensing.
Highlights
Innate lymphoid cells (ILC) have typical lymphocyte morphology, originate from the common lymphoid progenitor [1] and mirror the T-helper subsets in transcription factor dependence and cytokine production
We found that blister and blood ILC2 express a broad range of pattern recognition receptor (PRR) (Fig. 1A)
ILC2 NOD2 protein cellular expression was enhanced by stimulation with IL33 and prostaglandin D2 (PGD2) (Fig. 1G), in human blood ILC2 that had been isolated by flow cytometry
Summary
Innate lymphoid cells (ILC) have typical lymphocyte morphology, originate from the common lymphoid progenitor [1] and mirror the T-helper subsets in transcription factor dependence and cytokine production. Analysis of human skin biopsies and murine studies have established that skin trauma induces IL-33-dependent ILC2 proliferation, migration, and production of the epithelial growth factor amphiregulin [7,8,9]. In addition to passive release upon epithelial damage, type-2 inducer cytokines and skinspecific ILC2-activating cytokines (e.g. IL-18) are produced by keratinocytes following TLR sensing of atopic dermatitis (AD) skin-colonizing S. aureus [10]. Cutaneous NKp30+ILC2 sense increased expression of B7H6 in AD lesions and tumors, inducing type-2 cytokine production [9]. We use a human skin challenge model to investigate the role of PRR signaling to induce ILC2 cytokine production, with findings that show a previously unappreciated mechanism for ILC2 in cutaneous bacterial surveillance
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