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2016 ; 113
(37
): E5434-43
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Cd47-Sirp? interaction and IL-10 constrain inflammation-induced macrophage
phagocytosis of healthy self-cells
#MMPMID27578867
Bian Z
; Shi L
; Guo YL
; Lv Z
; Tang C
; Niu S
; Tremblay A
; Venkataramani M
; Culpepper C
; Li L
; Zhou Z
; Mansour A
; Zhang Y
; Gewirtz A
; Kidder K
; Zen K
; Liu Y
Proc Natl Acad Sci U S A
2016[Sep]; 113
(37
): E5434-43
PMID27578867
show ga
Rapid clearance of adoptively transferred Cd47-null (Cd47(-/-)) cells in
congeneic WT mice suggests a critical self-recognition mechanism, in which CD47
is the ubiquitous marker of self, and its interaction with macrophage signal
regulatory protein ? (SIRP?) triggers inhibitory signaling through SIRP?
cytoplasmic immunoreceptor tyrosine-based inhibition motifs and tyrosine
phosphatase SHP-1/2. However, instead of displaying self-destruction phenotypes,
Cd47(-/-) mice manifest no, or only mild, macrophage phagocytosis toward
self-cells except under the nonobese diabetic background. Studying our recently
established Sirp?-KO (Sirp?(-/-)) mice, as well as Cd47(-/-) mice, we reveal
additional activation and inhibitory mechanisms besides the CD47-SIRP? axis
dominantly controlling macrophage behavior. Sirp?(-/-) mice and Cd47(-/-) mice,
although being normally healthy, develop severe anemia and splenomegaly under
chronic colitis, peritonitis, cytokine treatments, and CFA-/LPS-induced
inflammation, owing to splenic macrophages phagocytizing self-red blood cells. Ex
vivo phagocytosis assays confirmed general inactivity of macrophages from
Sirp?(-/-) or Cd47(-/-) mice toward healthy self-cells, whereas they aggressively
attack toward bacteria, zymosan, apoptotic, and immune complex-bound cells;
however, treating these macrophages with IL-17, LPS, IL-6, IL-1?, and TNF?, but
not IFN?, dramatically initiates potent phagocytosis toward self-cells, for which
only the Cd47-Sirp? interaction restrains. Even for macrophages from WT mice,
phagocytosis toward Cd47(-/-) cells does not occur without phagocytic activation.
Mechanistic studies suggest a PKC-Syk-mediated signaling pathway, to which IL-10
conversely inhibits, is required for activating macrophage self-targeting,
followed by phagocytosis independent of calreticulin Moreover, we identified
spleen red pulp to be one specific tissue that provides stimuli constantly
activating macrophage phagocytosis albeit lacking in Cd47(-/-) or Sirp?(-/-)
mice.
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