Soluble bacterial lipopeptides suppress gasdermin D-associated IL-33 release in keratinocytes and atopic dermatitis in mice

The rising prevalence of allergic diseases over the last century has been linked to smaller families and the shift of populations from countryside to cities, leading to reduced exposure to environmental bacteria. We previously demonstrated that Staphylococcus aureus-derived Second immunoglobulin-binding protein (Sbi) drives type 2 immune responses and atopic dermatitis (AD). Here we show that contrary to current dogma, soluble lipopeptides, particularly diacylated lipopeptides released by Gram-positive bacteria in their stationary phase suppress type 2 immune responses in vitro and eczema in the NC/Tnd mouse model. The immunomodulatory activity of these lipopeptides is destroyed by lipoprotein lipase. Their mechanism of immunomodulation is independent of CD14 and toll-like receptor (TLR) signaling but rather associated with inhibition of caspase/gasdermin D (GSDMD)-mediated release of the interleukin (IL)-33 alarmin from the nucleus. Our findings help to explain why exposure to environmental bacteria and topical application of bacterial commensals suppresses AD. We suggest that soluble bacterial lipopeptides could be developed into a novel class of therapeutics for treatment of allergic diseases.