The pattern recognition receptor, Mincle, is essential for maintaining the M1 macrophage phenotype in acute renal inflammation

Kidney Int. 2017 Mar;91(3):587-602. doi: 10.1016/j.kint.2016.10.020. Epub 2016 Dec 22.

Abstract

Mincle (macrophage-inducible C-type lectin, Clec4e) is a transmembrane pattern recognition receptor involving the innate immunity, but its role in kidney disease is still unexplored. In the obstructed kidney of the unilateral ureteral obstruction model of renal injury, Mincle was specifically detected in the infiltrating M1 macrophages (CD68+iNOS+ cells) on day one but was rapidly reduced following reduction of M1 macrophages during the progression of kidney injury. Interestingly, Mincle-expressing macrophages were progressively increased in the cisplatin-induced acute kidney injury model, where iNOS expression was detected in the CD68+ cells following Mincle induction. Adaptive transfer of Mincle+ M1 macrophages largely promoted cisplatin-induced renal inflammation, which was prevented by the knockdown of Mincle in the transferred cells. Mincle was tightly regulated by TLR4/NF-κB signaling as evidenced by the binding of NF-κB/p65 to the promoter region of Mincle in LPS-primed macrophages. Blocking TLR4 or NF-κB suppressed LPS-induced Mincle expression on macrophages. Importantly, Mincle was found to be essential for maintaining the inflammatory phenotypes of M1 macrophages through the Syk signaling pathway since knockdown of Mincle or inhibition of Syk suppressed LPS-induced IL-1β, MCP-1, and iNOS expression. Thus, Mincle is induced specifically on M1 macrophages, where Mincle-Syk signaling promotes and maintains inflammatory phenotypes of M1 macrophages in acute renal inflammation. Hence, targeting Mincle may be a novel therapy for acute kidney injury associated with M1 macrophages.

Keywords: Clec4e; M1 macrophage; Mincle; TLR4/NF-κB/Syk signaling; acute kidney injury; inflammation; macrophage-inducible C-type lectin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Kidney Injury / genetics
  • Acute Kidney Injury / immunology
  • Acute Kidney Injury / metabolism*
  • Acute Kidney Injury / pathology
  • Adoptive Transfer
  • Animals
  • Antigens, CD / metabolism
  • Antigens, Differentiation, Myelomonocytic / metabolism
  • Binding Sites
  • Cisplatin
  • Disease Models, Animal
  • Gene Expression Regulation
  • Humans
  • Kidney / immunology
  • Kidney / metabolism*
  • Kidney / pathology
  • Lectins, C-Type / genetics
  • Lectins, C-Type / immunology
  • Lectins, C-Type / metabolism*
  • Macrophage Activation*
  • Macrophages / immunology
  • Macrophages / metabolism*
  • Macrophages / pathology
  • Macrophages / transplantation
  • Membrane Proteins / genetics
  • Membrane Proteins / immunology
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Nephritis / genetics
  • Nephritis / immunology
  • Nephritis / metabolism*
  • Nephritis / pathology
  • Nitric Oxide Synthase Type II / metabolism
  • Phenotype
  • Promoter Regions, Genetic
  • RAW 264.7 Cells
  • RNA Interference
  • Receptors, Pattern Recognition / genetics
  • Receptors, Pattern Recognition / immunology
  • Receptors, Pattern Recognition / metabolism*
  • Signal Transduction
  • Syk Kinase / metabolism
  • Time Factors
  • Toll-Like Receptor 4 / metabolism
  • Transcription Factor RelA / metabolism
  • Transfection
  • Ureteral Obstruction / complications

Substances

  • Antigens, CD
  • Antigens, Differentiation, Myelomonocytic
  • CD68 protein, mouse
  • Clecsf8 protein, mouse
  • Lectins, C-Type
  • Membrane Proteins
  • Receptors, Pattern Recognition
  • Rela protein, mouse
  • Tlr4 protein, mouse
  • Toll-Like Receptor 4
  • Transcription Factor RelA
  • Nitric Oxide Synthase Type II
  • Nos2 protein, mouse
  • Syk Kinase
  • Syk protein, mouse
  • Cisplatin