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2016 ; 113
(39
): 10944-9
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TLR9-mediated inflammation drives a Ccr2-independent peripheral monocytosis
through enhanced extramedullary monocytopoiesis
#MMPMID27621476
Weaver LK
; Chu N
; Behrens EM
Proc Natl Acad Sci U S A
2016[Sep]; 113
(39
): 10944-9
PMID27621476
show ga
Monocytes are innate immune cells that interact with their environment through
the expression of pattern recognition receptors, including Toll-like receptors
(TLRs). Both monocytes and TLRs are implicated in driving persistent inflammation
in autoimmune diseases. However, cell-intrinsic mechanisms to control
inflammation, including TLR tolerance, are thought to limit inflammatory
responses in the face of repeated TLR activation, leaving it unclear how chronic
TLR-mediated inflammation is maintained in vivo. Herein, we used a
well-characterized model of systemic inflammation to determine the mechanisms
allowing sustained TLR9 responses to develop in vivo. Monocytes were identified
as the main TLR9-responsive cell and accumulated in peripherally inflamed tissues
during TLR9-driven inflammation. Intriguingly, canonical mechanisms controlling
monocyte production and localization were altered during the systemic
inflammatory response, as accumulation of monocytes in the liver and spleen
developed in the absence of dramatic increases in bone marrow monocyte
progenitors and was independent of chemokine (C-C motif) receptor 2 (Ccr2).
Instead, TLR9-driven inflammation induced a Ccr2-independent expansion of
functionally enhanced extramedullary myeloid progenitors that correlated with the
peripheral accumulation of monocytes in both wild-type and Ccr2(-/-) mice. Our
data implicate inflammation-induced extramedullary monocytopoiesis as a
peripheral source of newly produced TLR9 responsive monocytes capable of
sustaining chronic TLR9 responses in vivo. These findings help to explain how
chronic TLR-mediated inflammation may be perpetuated in autoimmune diseases and
increase our understanding of how monocytes are produced and positioned during
systemic inflammatory responses.
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