Monocyte Migration To Sites Of Inflammation

Monocytes play an important role in the immune network as one of the first lines of defence against inflammatory challenge. Monocytes develop in the bone marrow, enter the circulation, and subsequently enter tissues of the body where they differentiate into tissue macrophages and dendritic cells. Under inflammatory conditions, the number of monocytes leaving the circulation doubles that under homeostatic conditions [52], CCL2/monocyte chemoattractant protein (MCP) -1 has been long known to mediate recruitment of monocytes into sites of inflammation. Lack of CCR2 expression in an experimental peritoneal inflammation model using a non-specific inflammatory stimulus, thioglycollate, results in an impaired recruitment of macrophages into the peritoneum [53], In addition, CCR2 deficient mice are unable to clear infection by intracellular bacteria, Listeria monocytogenes [53], Furthermore, macrophages play an important role in the development of protective cutaneous granulomas initiated by Leishmania major or Mycobacterium leprae [54]. Such early macrophage recruitment to sites of cutaneous granuloma formation has been shown to be mediated by MIP-loc/p chemokines released from neutrophils recruited by mast cell derived TNF-a [54],

Interestingly, CCL2/MCP-1 produced in inflamed skin is transported via lymph to the HEV of the draining lymph nodes, therefore mediating recruitment of monocytes into lymph nodes [55]. This suggests that chemokines have the potential to remotely control the immune network. CCL2/MCP-1 has also been implicated in macrophage trafficking to the central nervous system (CNS) under inflammatory conditions and in the pathogenesis of experimental autoimmune encephalomyelitis (EAE), where macrophages are thought to be the primary effector cells in mediating cellular pathology and tissue damage [56]. In particular, mice deficient in CCL2/ MCP-1 or its cognate receptor CCR2, show resistance to EAE [57-59].

Other non-lymphoid tissues such as breast, kidney, skin and gut have been shown to express

CXCL14/BRAK, which selectively recruits circulating monocytes in homeostasis, as well as monocytes activated by prostaglandin E2 (PGE2). CXCL14/breast and kidney-expressed chem-okine (BRAK), which is thought to be made constitutively by normal skin keratinocytes, dermal fibroblasts, as well as lamina propria cells [60], Monocytes cultured with PGE2 have been shown to gain chemotactic responsiveness to CXCL14/BRAK, while losing responsiveness to CCL2/ MCP-1, CCL5/regulated upon activation, normal T cell expressed and secreted (RANTES), and CXCL12/stromal cell-derived factor (SDF) -1 [60], The receptor for CXCL14/BRAK is yet unknown. The authors propose that once monocytes enter sites of inflammation, local secretion of PGE, polarizes monocytes to be responsive to high levels of CXCL14/BRAK.

Most recently, two functional subsets of monocytes with distinct migratory properties have been identified. Geissmann et al. [61] have identified a CX3CR1MCCR2 GR1 subset of monocytes characterized by CX^CRl-dependent recruitment to non-inflamed tissues such as spleen, lung, liver, and brain; as well as a short-lived CX3CRllowCCR2+GRl+ subset that is actively recruited to sites of inflammation in a model of intraperitoneal thioglycollate injection. However, Ancuta et al. [62] have shown that Fractalkine, but not MCP-1, plays an important role in transendothelial migration of a CD16+ subtype of monocytes, proposed to be dendritic cell precursors, via CXCRI under inflammatory challenge. Further evidence supports the role of Fractalkine in monocyte recruitment under inflammatory challenge. Fractalkine protein has been detected in atherosclerotic lesions and CXCR3 deficient mice have impaired macrophage recruitment to the vessel wall and decreased atherosclerotic lesion formation [63], In addition to Fractalkine, earlier evidence showed that KC (Gro-a), the ligand for CXCR2, but not MCP-1, significantly induced monocyte arrest on early atherosclerotic endothelium [64],

In addition to the above mentioned chemokines/chemokine receptors, other chemokines/ receptors have been implicated in the trafficking of monocyte dendritic cell precursors such as CXCR1, CXCR4 and CCR6 [65], Expression of inflammatory chemokines receptors CCR2, CCR5, CCR6, CXCR1, and CXCR2 allows immature dendritic cells to respond to inflammatory chemokines made by non-haematopoietic cells such as keratinocytes in the skin [65], These signals direct dendritic cells to enter lymph and travel to T -cell areas of draining lymph nodes. Furthermore, Pashenkov et al. [66] have implicated CXCR4, the receptor for SDF-1, in mediating trafficking of dendritic cells to cerebrospinal fluid by showing partial inhibition of dendritic cells trafficking by CXCR4 neutralizing antibodies.

Overall, monocytes and macrophages are recruited to sites of foreign or self-antigen by CCL2/MCP-1 through their expression of CCR2. However, other chemokines such as CXCL14/ BRAK and Fractalkine also have been shown to recruit monocytic macrophage precursors during both homeostasis and inflammation. Furthermore, monocyte dendritic cell precursors have been shown to be recruited by a number of chemokines such as IL-8, SDF-1 and MIP-3a in addition to MCP-1 and MIP-1 a/[i

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