β-Glucuronidase, a Regulator of Lyme Arthritis Severity, Modulates Lysosomal Trafficking and MMP-9 Secretion in Response to Inflammatory Stimuli

Abstract

The lysosomal enzyme beta-glucuronidase (Gusb) is a key regulator of Lyme-associated and K/B×N-induced arthritis severity. The luminal enzymes present in lysosomes provide essential catabolic functions for the homeostatic degradation of a variety of macromolecules. In addition to this essential catabolic function, lysosomes play important roles in the inflammatory response following infection. Secretory lysosomes and related vesicles can participate in the inflammatory response through fusion with the plasma membrane and release of bioactive contents into the extracellular milieu. Here we show that GUSB hypomorphism potentiates lysosomal exocytosis following inflammatory stimulation. This leads to elevated secretion of lysosomal contents, including glycosaminoglycans, lysosomal hydrolases, and Matrix Metalloproteinase 9, a known modulator of Lyme arthritis severity. This mechanistic insight led us to test the efficacy of Rapamycin, a drug known to suppress lysosomal exocytosis. Both Lyme and K/B×N-associated arthritis were suppressed by this treatment concurrent with reduced lysosomal release.

NK cell–derived GM-CSF potentiates inflammatory arthritis and is negatively regulated by CIS

“…Loss of MMP8 has been associated with exacerbation of arthritis due to its role in regulating neutrophil apoptosis ( Cox et al, 2010 ; García et al, 2010 ). CYP4F3, also known as leukotriene B4/LTB4 omega-hydroxylase 2, also negatively regulates inflammation by catalyzing the inactivation of LTB4 ( Bramwell et al, 2014 , 2015 ; Chou et al, 2010 ; Christmas et al, 1999 ). Taken together, these findings highlight CIS as a negative regulator of GM-CSF–mediated neutrophil effector cell functions.…”

“…Additionally, proteomic analysis of GM-CSF–primed CIS-deficient neutrophils revealed down-regulation of key enzymatic brakes of inflammation, such as MMP8 and CYP4F3, relative to WT neutrophils. Importantly, MMP8 has been shown to control neutrophil apoptosis and resolution of arthritis ( Cox et al, 2010 ; García et al, 2010 ), while CYP4F3 catalyzes the inactivation of pro-inflammatory LTB4 ( Bramwell et al, 2014 , 2015 ; Chou et al, 2010 ; Christmas et al, 1999 ). Reductions in these anti-inflammatory pathways in GM-CSF–primed CIS-deficient neutrophils are likely to have contributed to the exacerbation of STIA in CIS-deficient mice because joint LTB4 levels were elevated.…”

MicroRNA Expression Shows Inflammatory Dysregulation and Tumor‐Like Proliferative Responses in Joints of Patients With Postinfectious Lyme Arthritis

“…We suspect that in humans, genetic variables determine whether the response to B. burgdorferi infection elicits an appropriate wound repair response (B6-like) (37, 38) or a maladaptive inflammatory cellular response and arrest of wound repair processes (C3H-like) (39). For example, human patients who have a polymorphism in the TLR1 gene (1805GG), found primarily in the European Caucasian population, have higher levels of IFNγ/STAT1-dependent cytokines when infected with RST1 B. burgdorferi strains, and they have an increased frequency of post-infectious, antibiotic-refractory LA (40).…”

Pam3CSK4 Induces MMP-9 Expression in Human Monocytic THP-1 Cells

“…MMPs are the major proteases and their dysregulation is involved in the pathogenesis of several pathogensis disorders [29][30][31]. In obesity, MMP-9 may facilitate the infiltration of immune cells into the adipose tissue and could promote obesity-associated metabolic inflammation.…”