IL-6 effector function of group 2 innate lymphoid cells (ILC2) is NOD2 dependent

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Science Immunology  21 May 2021:
Vol. 6, Issue 59, eabe5084
DOI: 10.1126/sciimmunol.abe5084

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Skin sentinels

Group 2 innate lymphoid cells (ILC2) are the predominant ILC subset in the skin and are positioned to respond to barrier disruption. Hardman et al. examined the ability of ILC2 to directly sense skin pathogens. ILC2 from in vivo–challenged skin or peripheral blood showed an increase in NOD2 and TLR2 expression. ILC2 stimulated with a TLR2 agonist up-regulated IL-5 and IL-13 expression, but stimulation with both TLR2 agonist and Staphylococcus aureus muramyl dipeptide also induced IL-6 expression. Exposure of ILC2 to heat-killed skin-resident bacteria induced IL-6 expression, which was reduced by NOD2 pathway inhibition, and NOD2 signaling stimulated autophagy in ILC2. These findings define a role for ILC2 NOD2 in cutaneous bacterial sensing and regulation of IL-6 expression.


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.

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