Angiogenic and Arthritogenic Properties of the Soluble Form of CD13

Abstract

Aminopeptidase N/CD13 is expressed by fibroblast-like synoviocytes (FLS) and monocytes (MNs) in inflamed human synovial tissue (ST). This study examined the role of soluble CD13 (sCD13) in angiogenesis, MN migration, phosphorylation of signaling molecules, and induction of arthritis. The contribution of sCD13 was examined in angiogenesis and MN migration using sCD13 and CD13-depleted rheumatoid arthritis (RA) synovial fluids (SFs). An enzymatically inactive mutant CD13 and intact wild-type (WT) CD13 were used to determine whether its enzymatic activity contributes to the arthritis-related functions. CD13-induced phosphorylation of signaling molecules was determined by Western blotting. The effect of sCD13 on cytokine secretion from RA ST and RA FLS was evaluated. sCD13 was injected into C57BL/6 mouse knees to assess its arthritogenicity. sCD13 induced angiogenesis and was a potent chemoattractant for MNs and U937 cells. Inhibitors of Erk1/2, Src, NF-kB, Jnk, and pertussis toxin, a G protein-coupled receptor inhibitor, decreased sCD13-stimulated chemotaxis. CD13-depleted RA SF induced significantly less MN migration than sham-depleted SF, and addition of mutant or WT CD13 to CD13-depleted RA SF equally restored MN migration. sCD13 and recombinant WT or mutant CD13 had similar effects on signaling molecule phosphorylation, indicating that the enzymatic activity of CD13 had no role in these functions. CD13 increased the expression of proinflammatory cytokines by RA FLS, and a CD13 neutralizing Ab inhibited cytokine secretion from RA ST organ culture. Mouse knee joints injected with CD13 exhibited increased circumference and proinflammatory mediator expression. These data support the concept that sCD13 plays a pivotal role in RA and acute inflammatory arthritis.

Synovial fluid peptidase activity as a biomarker for knee osteoarthritis clinical progression

“…The potential importance of NAP is related to its expression by fibroblast-like synoviocytes in inflamed synovial tissue in humans, suggesting a role in acute inflammatory arthritis. 29 Regarding PSA, while there is a paucity of data, spinorphin, an endogenous enzyme inhibitor, has been reported to break down enkephalin and play a role in pain and inflammation. 44 The possible role of PSA in pain strengthens its clinical relevance, in that, as underlined by scientific societies, pain is an important clinical feature in deciding whether to indicate arthroplasty, and this is what motivated us to include it in our study.…”

“…aminopeptidase N, expressed by fibroblast-like synoviocytes) are present in synovial fluid and could play a role in OA. 29 As de Silveira et al 30 demonstrated, in an animal model of arthritis, joint inflammation was induced by activation of the renin-angiotensin system, but reduced by activation of angiotensin-converting enzyme-2/Ang-(1–7)/Mas receptor pathway.…”

Coronavirus Receptors as Immune Modulators

“…Indeed, Ab-mediated cross-linking of CD13 in mast cells leads to IL-6 production (82). Additionally, soluble CD13 is highly abundant in synovial fluid of rheumatoid arthritis patients, where it increases expression of proinflammatory cytokines (83)(84)(85)(86)(87)(88)(89)(90). With regard to HCoV-229E infection, treatment of primary human nasal and tracheal epithelial cells with glycopyrronium/formoterol/budesonide, a mixture of drugs used to treat chronic obstructive pulmonary disease caused by HCoV-229E infection, led to reduced CD13 expression, fewer acidic endosomes that are essential for the entry of HCoV-229E, as well as decreased production of inflammatory cytokines (79).…”

CD13/Aminopeptidase N Is a Potential Therapeutic Target for Inflammatory Disorders

“…CD13 can also be shed from the cell membrane by MMP-14 (25), and the resultant sCD13 functions by engaging GPCRs on cytokine-activated lymphocytes (19), MNs, ECs, and fibroblasts (26). However, the identity of such GPCRs has not CD13 also tethers the IQGAP1-ARF6-EFA6 complex on the plasma membrane to promote ARF6 activation, b1 integrin recycling, and cell migration.…”

“…yet been reported. With binding to GPCRs, sCD13 induces phosphorylation of Src, ERK1/2, and, to some extent, NF-kB, activating cell migration, angiogenesis, and other responses (26). Pertussis toxin, a GPCR inhibitor, significantly reduced chemotactic responses of cytokine-activated T cells (19) or monocytic cells as well as endothelial capillary morphogenesis in response to sCD13 (26).…”