Ph.D. Candidate Gachon University Incheon, Republic of Korea
Disclosure(s):
Kunhee Na, MS: No financial relationships to disclose
Introduction/Rationale: 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.
