2. Academic Validation
  3. Characterizing Kupffer Cell Production of CD5 Antigen-Like and Its Function on Regulating Migration of Natural Killer T Cells

Characterizing Kupffer Cell Production of CD5 Antigen-Like and Its Function on Regulating Migration of Natural Killer T Cells

  • Am J Pathol. 2025 Jul 8:S0002-9440(25)00235-4. doi: 10.1016/j.ajpath.2025.06.003.
Handan Hong 1,  Taojian Tu 1,  Diala Alhousari 1,  Lina He 1,  Richa Aggarwal 1,  Anketse Debebe 1,  Chien-Yu Chen 1,  Karam Ashouri 2,  Anastasia Martynova 2,  Christina Nakhoul 2,  Ali Rastegarpour 2,  Sina Baharlouei 3,  Dai Peng 3,  Eileen X Stile 3,  Meisam Razaviyayn 4,  Sze-Chuan Suen 3,  Enrique Cadenas 1,  Houda Alachkar 5,  Weiming Yuan 6,  Keigo Machida 6,  Hidekazu Tsukamoto 7,  Liyun Yuan 8,  Anthony El-Khoueiry 2,  Bangyan L Stiles 9
Affiliations

Affiliations

  • 1 Department of Pharmacology and Pharmaceutical Sciences, Mann School of Pharmacy, University of Southern California, Los Angeles, California.
  • 2 Division of Medical Oncology, Keck School of Medicine, University of Southern California, Norris Comprehensive Cancer Center, Los Angeles, California.
  • 3 Epstein Department of Industrial and Systems Engineering, Viterbi School of Engineering, University of Southern California, Los Angeles, California.
  • 4 Epstein Department of Industrial and Systems Engineering, Viterbi School of Engineering, University of Southern California, Los Angeles, California; Ming Hsieh Department of Electrical and Computer Engineering, Viterbi School of Engineering, University of Southern California, Los Angeles, California; Thomas Lord Department of Computer Science, Viterbi School of Engineering, University of Southern California, Los Angeles, California.
  • 5 Department of Clinical Pharmacy, Mann School of Pharmacy, University of Southern California, Los Angeles, California.
  • 6 Department of Immunology, Keck School of Medicine, University of Southern California, Norris Comprehensive Cancer Center, Los Angeles, California.
  • 7 Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, California; Department of Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California.
  • 8 Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California.
  • 9 Department of Pharmacology and Pharmaceutical Sciences, Mann School of Pharmacy, University of Southern California, Los Angeles, California; Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, California. Electronic address: bstiles@usc.edu.
PMID: 40639718 DOI: 10.1016/j.ajpath.2025.06.003
Abstract

CD5 antigen-like (CD5L) is a multifunctional glycoprotein characterized for its role in the lipid metabolism, particularly within macrophages. In the liver, CD5L strongly correlates with liver injury. This study explored the role of CD5L on liver lipid accumulation and inflammatory response. We show that CD5L promotes lipid uptake in hepatocytes and stellate cells. In multiple models of liver injury, expression of CD5L is associated with that of CLEC4F, a marker for liver macrophages, consistent with its role as a macrophage survival factor. Using transwell assay, we also demonstrated a novel function of CD5L on promoting migration of natural killer T cells. This effect is independent of CD36, the characterized receptor of CD5L. This effect is also observed with liver macrophages, which are the cellular source for CD5L, and blocking CD5L attenuates natural killer T cell migration induced by liver macrophages. Finally, we showed that plasma levels of CD5L correlate with poor patient response to immune check point therapy that is dependent on response of T-cell populations. In addition, plasma CD5L levels correlate with levels of steatosis and severity of steatotic liver injury. Because liver steatosis is correlated with poor patient response to immune checkpoint therapy, these data suggest that plasma CD5L levels may be used to predict patient response to immune checkpoint therapy.

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