Abstract
AA amyloidosis is a systemic disease that develops secondary to chronic inflammatory diseases Macrophages are often found in the vicinity of amyloid deposits and considered to play a role in both formation and degradation of amyloid fibrils. In spleen reside at least three types of macrophages, red pulp macrophages (RPM), marginal zone macrophages (MZM), metallophilic marginal zone macrophages (MMZM). MMZM and MZM are located in the marginal zone and express a unique collection of scavenger receptors that are involved in the uptake of blood-born particles. The murine AA amyloid model that resembles the human form of the disease has been used to study amyloid effects on different macrophage populations. Amyloid was induced by intravenous injection of amyloid enhancing factor and subcutaneous injections of silver nitrate and macrophages were identified with specific antibodies. We show that MZMs are highly sensitive to amyloid and decrease in number progressively with increasing amyloid load. Total area of MMZMs is unaffected by amyloid but cells are activated and migrate into the white pulp. In a group of mice spleen macrophages were depleted by an intravenous injection of clodronate filled liposomes. Subsequent injections of AEF and silver nitrate showed a sustained amyloid development. RPMs that constitute the majority of macrophages in spleen, appear insensitive to amyloid and do not participate in amyloid formation.
Highlights
AA amyloidosis is a systemic disease that develops in patients with chronic infectious and inflammatory disorders, e.g. rheumatoid arthritis, familial Mediterranean fever, and tuberculosis [1], with renal failure as main clinical outcome
Colocalization of serum amyloid A (SAA)/AA to lysosomes of monocytoid cells in mice with reactive amyloidosis implicate a role for lysosomes in amyloid formation [7,8], and in vitro studies have shown that SAA endocytosed by macrophages accumulates in intracellular vesicles and transform into amyloid [9]
We studied amyloid effects on red pulp macrophages (RPM), metallophilic marginal zone macrophages (MMZM) and
Summary
AA amyloidosis is a systemic disease that develops in patients with chronic infectious and inflammatory disorders, e.g. rheumatoid arthritis, familial Mediterranean fever, and tuberculosis [1], with renal failure as main clinical outcome. The main amyloid constituent in this form of amyloid disease is N-terminal fragments [2,3] of the acute phase reactant, serum amyloid A (SAA) [4]. Macrophages are often detected in close proximity to amyloid and considered significant for both the formation and degradation of aggregates. These processes appear to be independent of amyloid protein. Injections of macrophage colony-stimulating factor in brain of transgenic mice that develop Alzheimer’s disease led to increased number of microglia and decreased number of Ab deposits [13]
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