Delayed cutaneous wound healing in mice lacking solute carrier 11a1 (formerly Nramp1): correlation with decreased expression of secretory leukocyte protease inhibitor.
Control of macrophage functions by natural resistance-associated macrophage protein 1 (NRAMP1) has proven to be important for murine resistance to several intracellular pathogens, including Mycobacterium bovis BCG and Salmonella typhimurium, although the exact molecular mechanism of its action remains unknown. We identified secretory leukocyte protease inhibitor (SLPI) as a novel candidate gene whose expression is dependent on Nramp1 gene expression using B10A.Nramp1+/+ and B10A.Nramp1-/- macrophage cell lines in vitro, as well as mice bearing the resistance alleles (wild type (WT)) of the Nramp1 and mice with an ablated Nramp1 gene (knockout (KO)). We established that B10A.Nramp1+/+ cells spontaneously expressed a 10-fold higher level of SLPI messenger RNA (mRNA) compared to B10A.Nramp1-/- expression. Similarly, protein secretion was detected only in supernatants from B10A.Nramp1+/+ macrophages. Induction of SLPI in excisional cutaneous wounds and, most importantly, in macrophages infiltrating these wounds was significantly higher in Nramp1 WT mice compared to KO mice. These differences in SLPI expression in vivo correlated with a significant delay in the kinetics of wound healing in Nramp1 KO mice compared to WT controls. Taken together, these results suggest for the first time that Nramp1 controls macrophage SLPI mRNA and protein expression, and can also have an important effect on the kinetics of wound healing.
Thuraisingam
Thusanth
T
Department of Human Genetics, Montreal General Hospital Research Institute, McGill University, Montreal, Quebec, Canada.
Sam
Hakeem
H
Moisan
Jacques
J
Zhang
Yi
Y
Ding
Aihao
A
Radzioch
Danuta
D
D000818:Animals; D027682:Cation Transport Proteins / Q000032:analysis / Q000172:deficiency* / Q000235:genetics; D015536:Down-Regulation; D005786:Gene Expression Regulation; D008264:Macrophages / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D053491:Proteinase Inhibitory Proteins, Secretory; D011506:Proteins / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D053481:Secretory Leukocyte Peptidase Inhibitor; D012867:Skin / Q000166:cytology; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D014945:Wound Healing / Q000235:genetics*; D000099173:Natural Resistance-associated Macrophage Protein 1
D027682:Cation Transport Proteins; D053491:Proteinase Inhibitory Proteins, Secretory; D011506:Proteins; D012333:RNA, Messenger; D053481:Secretory Leukocyte Peptidase Inhibitor; D016212:Transforming Growth Factor beta; D000099173:Natural Resistance-associated Macrophage Protein 1; C506815:Slpi protein, mouse