Chitosan leads to downregulation of YKL‐40 and inflammasome activation in human macrophages

Abstract

Chitosan, the deacetylated derivative of chitin, is used as biomaterial in diverse settings. It is also found on pathogens and can be proinflammatory. Shorter derivatives of chitosan can be generated chemically or enzymatically, chitosan oligosaccharides (ChOS). There is variation in the chemical composition of ChOS, including size distribution, but in general, they have been described as inert or anti-inflammatory. Active human chitinases can cleave chitin and chitosan, while inactive chitinases bind both but do not cleave. Both active and inactive chitinases have important roles in the immune response. The inactive chitinase YKL-40 is expressed highly during inflammation and has been proposed as a marker of poor prognosis. YKL-40 acts as a negative regulator of the inflammasome and as a positive regulator of angiogenesis. Levels of YKL-40 can therefore regulate levels of inflammation, the extent of angiogenesis, and the process of inflammation resolution. This study shows that chitosan leads to reduced secretion of YKL-40 by primary human macrophages and that this is concomitant with inflammasome activation. This was most pronounced with a highly deacetylated ChOS. No effect on the secretion of the active chitinase Chit-1 was detected. Smaller and more acetylated ChOS did not affect YKL-40 levels nor inflammasome activation. We conclude that this effect on the levels of YKL-40 is a part of the proinflammatory mechanisms of chitosan and its derivatives.

Progress in the Development of Chitosan-Based Biomaterials for Tissue Engineering and Regenerative Medicine

“…CS has an immunomodulatory effect which is important for the wound healing process and depends on DD [33]. It was shown that micro-and nano-sized CS particles induce inflammasome formation by macrophages [33][34][35][36]. In contrast, macro-sized CS scaffolds inhibit the release of IL-1β and thus the formation of inflammasomes in mouse and human macrophages in vitro [37], making the use of macro-sized CS scaffolds rational when excessive inflammation is present.…”

Modification of primary amines to higher order amines reduces in vivo hematological and immunotoxicity of cationic nanocarriers through TLR4 and complement pathways

“…Prior reports have evaluated nanoparticle toxicity by measuring in vitro innate immune activation in some ex vivo immune cells [26,27,[34][35][36], ex vivo complement activation in serum [30,37,38], and changes in the protein corona after ex vivo incubation with serum [39][40][41] There are also a handful of studies that has reported that cationic polymers induce in vivo innate immune responses. However, comprehensive evaluation and relative contributions of hematological, hepatic, and immune reactions to the overall systemic toxicity profile of cationic polymer nanoparticles, and mechanism to alleviate them, has not been studied.. [25,28] Although researchers have evaluated the effect of various small molecule modifications on the in vitro cytotoxicity of cationic nanoparticles, their effects on in vivo systemic toxicity, are poorly understood.…”

“…Chitosan nanoparticles also increased serum levels of TNF-a and IL-1b, which is in agreement with studies demonstrating that chitosan activates the inflammasome pathway. [28,35] [36] IAA modification prevented upregulation of IL-6, CXCL1, and IL-1b by chitosan nanoparticleswhich indicate that as with bPEI, IAA reduces innate immune activation by chitosan. At the same time, IAA modification also increased neutrophil uptake of chitosan nanoparticles and in vivo complement activation.…”

Influence of YKL‑40 gene RNA interference on the biological behaviors of endometrial cancer HEC‑1A cells

“…Elevated levels of serum YKL-40 protein have been reported in a number of other types of cancer, including glioma (11) cholangiocarcinoma (12), colorectal cancer (13), non-small cell lung cancer (14), renal cell cancer (15) and osteosarcoma (16). YKL-40 may also be expressed within local inflammatory cells in inflamed tissues (17,18) and it is considered to be a biomarker in inflammatory disease. The YKL-40 gene can regulate the extent of inflammation, and angiogenesis, and the process of inflammation resolution.…”