A microglial LCN2-MC4R signaling axis drives silica-induced neuronal damage via C1q release

  • J Neuroinflammation. 2026 Jan 23;23(1):70. doi: 10.1186/s12974-026-03695-5.
Xia Li  #  1  2  3  4 ,  Zihao Xie  #  2  3  4 ,  Hangbing Cao  1 ,  Fei Wang  4 ,  Ruiqing Yan  1 ,  Jianxin Wang  4 ,  Chao Liu  4 ,  Jialing Wang  5 ,  Min Mu  1  2  3 ,  Yan Liu  1  2  3 ,  ShanShan Ling  1 ,  Huiyu Ye  6 ,  Xinrong Tao  7  8  9  10
Affiliations
  • 1. School of Public Health, Anhui University of Science and Technology, Hefei, Anhui, 231131, China.
  • 2. Joint Research Center for Occupational Medicine and Health of IHM, Anhui University of Science and Technology, Huainan, 232001, China.
  • 3. Key Laboratory of Industrial Dust Prevention and Control, Occupational Safety and Health, Ministry of Education, Anhui University of Science and Technology, Huainan, 232001, China.
  • 4. School of Medicine, Anhui University of Science and Technology, Huainan, Anhui, 232001, China.
  • 5. Anhui University of Science and Technology First Affiliated Hospital, Huainan, 230026, China.
  • 6. School of Public Health, Anhui University of Science and Technology, Hefei, Anhui, 231131, China. [email protected].
  • 7. School of Public Health, Anhui University of Science and Technology, Hefei, Anhui, 231131, China. [email protected].
  • 8. Joint Research Center for Occupational Medicine and Health of IHM, Anhui University of Science and Technology, Huainan, 232001, China. [email protected].
  • 9. Key Laboratory of Industrial Dust Prevention and Control, Occupational Safety and Health, Ministry of Education, Anhui University of Science and Technology, Huainan, 232001, China. [email protected].
  • 10. Anhui University of Science and Technology First Affiliated Hospital, Huainan, 230026, China. [email protected].
  • # Contributed equally.
PMID: 41578331 DOI: 10.1186/s12974-026-03695-5
Abstract

Silica exposure precipitates irreversible lung injury; however, its long-term neurological sequelae—and the microglial mechanisms underlying these effects—remain poorly understood. Here, we demonstrate that inhaled crystalline silica induces persistent hippocampal inflammation, anxiety- and depression-like behaviors, and neuronal loss in mice. Bulk RNA Sequencing, immunophenotyping, and pharmacological depletion studies revealed that microglia are the primary source of complement C1q in silica-exposed brains. Mechanistically, silica-induced lipocalin-2 (LCN2) engages the melanocortin-4 receptor (MC4R) on microglia, activating a cAMP/PKA/NF-κB cascade that transcriptionally upregulates C1q. Pharmacological blockade of MC4R (using PF) abolished C1q overproduction, normalized brain-derived neurotrophic factor levels, and restored both synaptic integrity and behavioral performance. Our findings establish the LCN2–MC4R–C1q axis as a critical microglial pathway in silica-related neurotoxicity and identify MC4R antagonism as a promising, readily translatable intervention for occupational neuroinflammation.

Supplementary Information: The online version contains supplementary material available at 10.1186/s12974-026-03695-5.

Keywords
C1q; LCN2; Lung-brain axis; MC4R; Microglia; Neuroinflammation.
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