CD14 directs Fas-mediated apoptosis in dendritic cells to restrain neutrophil-driven psoriatic inflammation 2266853

Abstract

Abstract Introduction Immune cell turnover is vital for resolving chronic inflammation like psoriasis, which is driven by DCs. CD14, known as a TLR4 co-receptor for activation, was hypothesized to be a molecular switch, coupling pro-apoptotic Fas signaling to immune resolution. This study defines CD14’s cell-type-specific role in regulating Fas-mediated DC apoptosis and its impact on psoriatic inflammation and neutrophil recruitment. Methods Psoriasis was induced using the IMQ mouse model; severity and neutrophil infiltration were quantified. Conditional Knockout (CKO) models achieved cell-type-specific CD14 deletion in dDCs, LCs, and Mφs. Mechanistic analysis included Caspase-8 quantification in murine skin lesion protein extracts. Signaling redirection was confirmed via NF-κB p65 nuclear translocation and chemokine expression (Cxcl1, Cxcl2) after Fas ligation. Results CD14 expression inversely correlated with disease severity and neutrophil infiltration. CKO analysis confirmed a dermal DC-specific role: CD14 deficiency only in dDCs (dDC-CKO) exacerbated inflammation and led to a massive influx of neutrophils. CD14 was critical for promoting caspase-8-dependent Fas signaling, enabling DC apoptosis. In CD14-deficient dDCs, the Fas signal was redirected toward pro-inflammatory NF-κB pathways, amplifying the inflammatory loop via robust chemokine expression. Conclusion CD14 acts as a critical, dDC-specific molecular switch, balancing inflammation and resolution. It facilitates caspase-8 activation, driving efficient Fas-mediated DC apoptotic clearance. In its absence, the Fas signal is corrupted, activating NF-κB, which sustains inflammation by amplifying neutrophil recruitment and exacerbating pathology. This reveals a novel CD14 role in coupling apoptotic turnover to immune resolution, positioning it as a selective therapeutic target for chronic skin inflammation. Funding Source This study was supported by National Research Foundation of Korea (NRF) grants funded by the Ministry of Science and ICT (2023R1A2C2002522 to Y.J.; and 2021R1A5A2030333 to Y.K., Y.L., S.R., B.O., I.H., H.K., and Y.J.) and by the Ministry of Education (RS-2024-00411734 to K.N.). Topic Categories Innate Immune Responses and Host Defense: Cellular Mechanisms (INC)