Role of chitin and chitinase/chitinase-like proteins in inflammation, tissue remodeling, and injury

Abstract

The 18 glycosyl hydrolase family of chitinases is an ancient gene family that is widely expressed from prokaryotes to eukaryotes. In mammals, despite the absence of endogenous chitin, a number of chitinases and chitinase-like proteins (C/CLPs) have been identified. However, their roles have only recently begun to be elucidated. Acidic mammalian chitinase (AMCase) inhibits chitin-induced innate inflammation; augments chitin-free, allergen-induced Th2 inflammation; and mediates effector functions of IL-13. The CLPs BRP-39/YKL-40 (also termed chitinase 3-like 1) inhibit oxidant-induced lung injury, augments adaptive Th2 immunity, regulates apoptosis, stimulates alternative macrophage activation, and contributes to fibrosis and wound healing. In accord with these findings, levels of YKL-40 in the lung and serum are increased in asthma and other inflammatory and remodeling disorders and often correlate with disease severity. Our understanding of the roles of C/CLPs in inflammation, tissue remodeling, and tissue injury in health and disease is reviewed below.

Figure 1

Immune and regulatory effects of chitin, chitinases (C), and chitinase-like proteins (CLP). Chitin is a potent stimulator of innate immune responses and subsequent tissue injury. Chitin-free antigens are also able to induce the innate reactions that, in turn, lead to adaptive immune responses. When appropriately managed, these responses lead to tissue healing. When excessive injury or repair occurs, tissue fibrosis can ensue. C/CLP can inhibit (−) chitin-induced innate immune and injury responses. The ability of AMCase to directly degrade chitin via its chitinase activity and to inhibit epithelial cell apoptosis via a chitinolytic-independent mechanism and the ability of BRP-39/YKL-40 to inhibit oxidant-induced injury are examples of this regulation. Simultaneously, C/CLP-like acidic mammalian chitinase (AMCase) and BRP-39/YKL-40 enhance adaptive immune responses to chitin-free moieties, thereby ensuring the development of selective antigen-specific immunity. This has been studied most intensively with BRP-39/YKL-40, which enhance antigen sensitization, augment the survival of inflammatory cells, and induce alternative (M2) macrophage differentiation. C/CLP are further induced during the type 2 immune response, and their ability to inhibit structural cell apoptosis, to induce macrophage differentiation, and to aid in the production of TGF-β₁ may also contribute to healing and fibrosis.

Figure 2

Chitin regulation of macrophage proinflammatory [tumor necrosis factor (TNF)-α] and anti-inflammatory [interleukin (IL)-10] cytokine production. Chitin stimulates the expression of TNF-α and IL-10 in a size-dependent manner. Large chitin is inert, and intermediate-sized chitin (40–70 µm) is a powerful stimulator of TNF. This activation is mediated mainly via a Toll-like receptor-2–nuclear factor-κB (TLR-2-NF-κB) pathway, with lesser contributions from spleen tyrosine kinase (Syk). In contrast, small chitin (<40 µm, usually 2–10 µm) is a potent stimulator of IL-10 production. This inductive event is mediated largely via a dectin-1-Syk pathway, with lesser contributions from TLR-2 and NF-κB.

Figure 3

Contributions of BRP-39/YKL-40 to allergen-induced Th2 inflammation and tissue remodeling. At sites of adaptive Th2 inflammation, cytokines such as interleukin (IL)-13 stimulate BRP-39/YKL-40 production in macrophages and epithelial cells. BRP-39/YKL-40, in turn, contribute to this response by preventing macrophage apoptosis and inducing alternative (M2) macrophage differentiation, by increasing the number of and activating local dendritic cells (DC), and by inhibiting Th2 cell apoptosis. The Th2 cytokines that are then produced induce chemokines and transforming growth factor (TGF)-β₁, which contribute to inflammation, remodeling, and healing.

Figure 4

The proposed signaling pathways of YKL-40 in regulating angiogenesis and cellular proliferation. BRP-39 binds to the heparan sulfate (HS) of Syndecan-1, a major cell surface proteoglycan. Along with integrin αvβ3, such binding activates focal adhesion kinase (FAK). Phosphorylated FAK (p-FAK) activates downstream signaling molecules, including mitogen-activated protein (MAP) kinase Erk (p-Erk), phosphatidylinositol 3 kinase (p-PI3K), and Akt (p-Akt). Such activation induces cellular proliferation, adhesion, and survival, all of which contribute to the development and progression of angiogenesis. Similar pathways may contribute to tissue-remodeling responses such as those seen in fibrosis.