cathepsin-g and Arthritis--Juvenile

Chromatin undergoes extensive reprogramming during immune cell differentiation. Here we report the repression of controlled histone H3 amino terminus proteolytic cleavage (H3ΔN) during monocyte-to-macrophage development. This abundant histone mark in human peripheral blood monocytes is catalyzed by neutrophil serine proteases (NSPs) cathepsin G, neutrophil elastase and proteinase 3. NSPs are repressed as monocytes mature into macrophages. Integrative epigenomic analysis reveals widespread H3ΔN distribution across the genome in a monocytic cell line and primary monocytes, which becomes largely undetectable in fully differentiated macrophages. H3ΔN is enriched at permissive chromatin and actively transcribed genes. Simultaneous NSP depletion in monocytic cells results in H3ΔN loss and further increase in chromatin accessibility, which likely primes the chromatin for gene expression reprogramming. Importantly, H3ΔN is reduced in monocytes from patients with systemic juvenile idiopathic arthritis, an autoinflammatory disease with prominent macrophage involvement. Overall, we uncover an epigenetic mechanism that primes the chromatin to facilitate macrophage development.

Topics: Adolescent; Arthritis, Juvenile; Cathepsin G; Cell Differentiation; Cell Nucleus; Child; Child, Preschool; Chromatin; CRISPR-Cas Systems; Enzyme Assays; Epigenesis, Genetic; Epigenomics; Female; Gene Knockout Techniques; Histones; Humans; Jurkat Cells; Leukocyte Elastase; Leukocytes, Mononuclear; Macrophages; Male; Myeloblastin; Primary Cell Culture; Proteolysis; Recombinant Proteins; RNA-Seq; THP-1 Cells; Young Adult

Peroxidase-anti-peroxidase (PAP) staining and specific antibodies against cathepsin G and elastase from polymorphonuclear leukocytes (PMN) were applied to pannus-free and microscopically intact superficial articular cartilage. Restricted local deposits containing cathepsin G and elastase were found in three of ten patients with seropositive rheumatoid arthritis (RA), in one of three patients with seronegative RA and in one patient with juvenile chronic arthritis (JCA). Similarly, localized deposits of IgG and C3 were found in the patients with seropositive RA and JCA, but not in the patient with seronegative RA. Adjacent sections exhibited esterase activity in and around the PMN. In proteinase-positive areas from patients with seropositive RA the inhibitors alpha 1-proteinase inhibitor (alpha 1-PI) and alpha 2-macroglobulin (alpha 2-MG) were present in two of three and one of three patients, respectively. In JCA only alpha 1-proteinase inhibitor was present, and in seronegative RA no inhibitors were found. No staining of articular cartilage was observed in a patient with psoriatic arthritis. One of three cases with osteoarthritis exhibited patchy superficial staining for IgG only. In articular cartilage covered by pannus, in three patients with seropositive RA, in one with seronegative RA and in the patient with JCA a few regions with variably dense PMN infiltrates were observed. Cathepsin G, elastase and esterase activity were found in and around the PMN. In one of the three patients with seropositive RA the adjacent cartilage-pannus junction exhibited distinct staining for cathepsin G and elastase, but not for IgG/C3 and proteinase inhibitors.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Arthritis, Juvenile; Arthritis, Rheumatoid; Cartilage, Articular; Cathepsin G; Cathepsins; Complement C3; Histocytochemistry; Humans; Immunoglobulin G; Immunohistochemistry; Neutrophils; Osteoarthritis; Pancreatic Elastase; Serine Endopeptidases