An update on Ym1 and its immunoregulatory role in diseases

Abstract

Ym1 is a rodent-specific chitinase-like protein (CLP) lacking catalytic activity, whose cellular origins are mainly macrophages, neutrophils and other cells. Although the detailed function of Ym1 remains poorly understood, Ym1 has been generally recognized as a fundamental feature of alternative activation of macrophages in mice and hence one of the prevalent detecting targets in macrophage phenotype distinguishment. Studies have pointed out that Ym1 may have regulatory effects, which are multifaceted and even contradictory, far more than just a mere marker. Allergic lung inflammation, parasite infection, autoimmune diseases, and central nervous system diseases have been found associations with Ym1 to varying degrees. Thus, insights into Ym1's role in diseases would help us understand the pathogenesis of different diseases and clarify the genuine roles of CLPs in mammals. This review summarizes the information on Ym1 from the gene to its expression and regulation and focuses on the association between Ym1 and diseases.

Keywords: Ym1/Chil3; chitinase like protein; immunoregulatory roles; inflammation related diseases; innate immunity.

Figure 1

The information of Chil3 gene, RNA and protein. Chil3 gene is situated in the F2.2 region of mouse chromosome 3, it is composed of 20,011 pairs of bases, containing 11 exon sequences, which are 1,539bp in length. Four STAT binding sites are located near exon 1. The 1,197nt CDS sequence encodes the Ym1 protein containing 398 residues. Ym1 protein, excluding the first 21 leading peptides and the last 4 carboxyl terminal residues, can be divided into a large β/α barrel (TIM barrel) domain and a small α+β domain. Ym1 also has several carbohydrate-interacting residues though it has no chitinase activity, and these residues are marked on the diagram.

Figure 2

Expressing cells of Ym1 in mice under physiological and pathophysiological conditions. Brain produces Ym1 by M2-typed microglia normally, by microglia in the parasitic infection and autoimmune neuroinflammation, and by microglia, Mφ and neutrophils in injuries. Lungs express Ym1 by alveolar macrophages (AMs) and/or neutrophils in normal, allergic lung inflammation and parasitic conditions. Thoracic cavity and peritoneal cavity express Ym1 in parasite infection respectively by thoracic lavage cells and Mφ in peritoneal exudative cells. Spleen and bone marrow are also main normal origins of Ym1 performed by immature neutrophils. The former also produces increased Ym1 in Mφ during parasite infection, and the latter does it by monocytes when repairing tissue injuries.

Figure 3

Schematic regulation of Ym1 expression. Various cytokines, drugs, microbial antigens are possible regulators. IL-4 and IL-13, the popular M2 drivers, were confirmed to promote Ym1 expression in both the in vitro and in vivo studies. TGF-β, Bm-MIF-1, LPS and Simvastatin were also found to be associated with Ym1 upregulation, and IFN-γ might correlate with its downregulation, while divergent views of dexamethasone remain in place. However, how Ym1 expression is fine-tuned by these signals remains elusive. The figure particularly illustrates the well-studied IL-4/STAT6 pathway. When stimulated by IL-4, STAT6 is phosphorylated, forming a homodimer and translocating to the nucleus, activating the gene transcription of Chil3. STAT6 can further activate PPAR-γ, which enhances Chil3 expression cooperatively.

Figure 4

Understanding of Ym1 behavior in allergic lung inflammation in mice. The overall effect of Ym1 in Th2 allergic lung inflammation is intensifying eosinophil recruitment. Ym1 plays that in a combinatorial manner. Ym1 depresses 12/15(S)-lipoxygenase (12/15-LOX) in CD4⁺ T cells and its catalysate 12-hydroxyeicosatetraenoic acid (12(S)-HETE), leading to the rise of Th2 cytokines. And Ym1 limits M2 polarization by downregulating the activation of STAT6 and PPAR-γ in macrophages. It might also regulate phenotypes directly by digesting glycosaminoglycan on macrophage surface. Matrix metalloproteinase (MMP) 2/9 engage in this system as Ym1 catalytic crackers, whose products may help to eosinophil recruitment. Ym1 recruits neutrophils as well, which may depend on IL-17 responses and contribute to lung inflammation. At the end of allergic lung inflammation, Ym1 may affect fibrosis to some extent.

Figure 5

Putative functions of Ym1 in the central nervous system diseases. Various inflammatory stimuli promote the expression of Ym1, including bacterial infection, traumatic injury, ischemic stroke, aging and certain cytokines released from the surrounding cells. In the CNS, Ym1 is expressed and secreted by alternatively activated myeloid cells, including resident microglia, recruited macrophages, and even a subpopulation of neutrophils. Ym1 is proposed to facilitate extracellular matrix (ECM) remodeling for its binding specificity to particular components like heparan sulfate. In demyelinating diseases, Ym1 may bind to epidermal growth factor receptor (EGFR) of the neural stem cells (NSCs) and activate the Ym1-EGFR-Pyk2 pathway, leading to oligodendrogenesis. The Ym1-expressing neutrophils display increased ability to infiltrate the ischemic core and undergo phagocytosis, thereby contributing to inflammation resolution and neuroprotection.