Date of Award
Open Access Thesis
Medical Doctor (MD)
Background: Following kidney injury, macrophages that have infiltrated the kidney undergo a transition from an initial proinflammatory state to a pro-reparative one characterized by the expression of arginase-1 (Arg 1), mannose receptor (Mrc1) and macrophage scavenger receptor-1 (Msr1). Granulocyte-macrophage colony-stimulating factor (GM-CSF) is an essential tubular-cell-derived determinant of the pro-reparative phenotype. However, it remains unclear what additional, if any, signals macrophages are integrating to maximally induce arginase-1.
Hypothesis: (1) The addition of cellular debris as a tubular cell cast mimetic will augment Arg1 expression in GM-CSF stimulated bone marrow derived macrophages; (2) Toll-like-receptors 2/4 transduce the debris signal from (1) and serve as the co- stimulatory signal in concert with GM-CSF to increase Arg1 expression.
Methods: Wildtype and TLR 2/4 knock-out macrophages were cultured in the presence of GM-CSF in the presence or absence of tubular cell debris to determine the relative expression of arginase-1 in macrophages.
Results: In cultured macrophages exposed to GM-CSF, the addition of cellular debris showed a significantly higher mRNA expression of Arg1, sometimes comparable to macrophages cultured with primary cultured renal cells (PCRC) with apical debris mimicking tubular casts. TLR 2/4 KO macrophages had an abrogation of Arg1 mRNA expression relative to wildtype macrophages cultured with GM-CSF and debris. However, no difference in levels of Mrc1 expression was seen.
Doilicho, Natnael Beyene, "Toll-Like Receptors 2/4 Directly Co-Stimulate Arginase-1 Induction Critical For Macrophage-Mediated Renal Tubule Regeneration" (2023). Yale Medicine Thesis Digital Library. 4177.
This Article is Open Access