Abstract
Neuroinflammation significantly contributes to Amyotrophic Lateral Sclerosis (ALS) pathology. In lieu of this, reports of elevated chitinase levels in ALS are interesting, as they are established surrogate markers of a chronic inflammatory response. While post-mortem studies have indicated glial expression, the cellular sources for these moieties remain to be fully understood. Therefore, the objective of this pilot study was to examine whether the peripheral immune system also contributes to chitinase dysregulation in ALS. The temporal expression of CHIT1, CHI3L1, and CHI3L2 in non-polarized monocyte-derived macrophages (MoMas) from ALS patients and healthy controls (HCs) was examined. We demonstrate that while CHIT1 and CHI3L1 display similar temporal expression dynamics in both groups, profound between-group differences were noted for these targets at later time-points i.e., when cells were fully differentiated. CHIT1 and CHI3L1 expression were significantly higher in MoMas from ALS patients at both the transcriptomic and protein level, with CHI3L1 levels also being influenced by age. Conversely, CHI3L2 expression was not influenced by disease state, culture duration, or age. Here, we demonstrate for the first time, that in ALS, circulating immune cells have an intrinsically augmented potential for chitinase production that may propagate chronic neuroinflammation, and how the ageing immune system itself contributes to neurodegeneration.
Highlights
Amyotrophic Lateral Sclerosis (ALS) is a fatal and relentlessly progressive neurodegenerative disorder
The temporal regulation patterns observed here are in keeping with previous studies; CHIT1 and Chitinase 3-Like 1 (CHI3L1) are minimally expressed in monocytes and highly upregulated during later stages of macrophage differentiation [14, 15]
Monocytes from ALS patients are more readily differentiated toward an M1-like phenotype, wherein they produce higher levels of pro-inflammatory cytokines, including Tumor Necrosis Factor alpha (TNF-α) and IL-6, than macrophages differentiated from healthy controls (HCs) monocytes [5]
Summary
Amyotrophic Lateral Sclerosis (ALS) is a fatal and relentlessly progressive neurodegenerative disorder. Clinically characterized by the loss of both upper and lower motor neurons, it is a multi-systemic condition driven by several cell non-autonomous processes. Glial dysregulation in particular can exacerbate disease progression and is necessary for motor neuronal death to occur [1,2,3]. Multiple lines of evidence have shown that this dysregulation extends to the peripheral innate immune system. Patient monocytes have a pro-inflammatory transcriptomic profile [4], secrete increased levels of pro-inflammatory cytokines [5], and can infiltrate the central nervous system (CNS) [6]; these alterations can influence disease progression.
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