Resident Cell Chemokine Expression Serves as the Major Mechanism for Leukocyte Recruitment During Local Inflammation

Abstract

The mechanistic relationships between initiating stimulus, cellular source and sequence of chemokine expression, and leukocyte recruitment during inflammation are not clear. To study these relationships in an acute inflammatory process, we challenged a murine air pouch with carrageenan. A time-dependent increase in TNF-␣, monocyte chemottractant protein-1 (MCP-1), macrophage-inflammatory protein-1␣ (MIP-1␣), RANTES, KC, and MIP-2 was found in the exudates preceding cell recruitment, but displaying different kinetic profiles. Air pouches generated for 2, 6, or 9 days before initiating inflammation demonstrated a proportional increase in the number of cells lining the cavities. Two hours after carrageenan stimulation, the synthesis of TNF-␣ and all chemokines but RANTES increased in proportion to the lining cellularity, although no differences in infiltrating leukocytes were found, suggesting that the early source of these mediators is resident cells. To assess the contribution of neutrophils to chemokine synthesis at later time points, we used neutropenic animals. Neutrophil depletion caused a decrease in TNF-␣ (51%), KC (37%), MIP-1␣ (30%), and RANTES (57%) levels and a 2-fold increase in monocytes 4 h after challenge. No effect on MIP-2 and MCP-1 levels was observed. The selective blockade of CXCR2 or CCR1 inhibited neutrophil recruitment by 74% and 54%, respectively, without a significant inhibition of monocytes. A differential effect on TNF-␣ and MCP-1 levels was observed after these treatments, indicating that the two receptors did not subserve a mere redundant chemotactic role. Overall, our results suggest that chemokines synthesized by resident cells play an important role in the evolution of the inflammatory response.

β2‐Adrenergic receptor regulation of human neutrophil function is sexually dimorphic

“…We observed that cell culture supernatants collected from isoprenaline-stimulated neutrophils initiated chemotaxis in neutrophils from both males and females. This effect was antagonized, in females, by SB225002, a selective CXCR2 antagonist, and by a CXCR2 antibody, which has been shown to markedly inhibit IL-8-induced neutrophil migration in murine models of inflammation (Garcia-Ramallo et al, 2002). However, while b 2 -adrenergic receptor agonists can increase IL-8 production (Linden, 1996;Kavelaars et al, 1997;Prause et al, 2003), this did not appear to be the mechanism of isoprenaline-induced chemotaxis in our study.…”

The Arthritis Severity Quantitative Trait Loci Cia4 and Cia6 Regulate Neutrophil Migration into Inflammatory Sites and Levels of TNF-α and Nitric Oxide

“…TNF-␣ is also a known chemotactic factor for neutrophils (46,47), and both activates endothelial cells and increases the expression of adhesion molecules (48, 49) further promoting leukocyte transmigration. Increased levels of TNF-␣ can be detected as early as 2h after the carrageenan injection in air pouches and precede the neutrophilic infiltration (50), supporting the concept of a key role in chemoattraction of these cells (47). Pouch lining macrophages, mast cells and fibroblasts contribute to the early levels of TNF-␣.…”

Mycobacterium bovis Bacillus Calmette-Guérin Vaccination Mobilizes Innate Myeloid-Derived Suppressor Cells Restraining In Vivo T Cell Priming via IL-1R–Dependent Nitric Oxide Production

“…The nature of extravasation kinetics (25) and interplay between the different subsets remains unclear (26,27). We examined the effect of neutrophils on the recruitment of CD11b + Ly-6C int Ly-6G 2 cells to the dermis in CX3CR1 +/GFP mice.…”

“…Upon disruption of homeostasis, the content of the inflammatory cell infiltrate must be tightly regulated. It is widely accepted that neutrophils infiltrate the lesion first and are swiftly followed by MOs, although the role played by neutrophils in the control of MO recruitment is unclear (26,27,41). The poor specificity of anti-Gr1 (Ly-6C/Ly-6G) Ab has contributed to confusion in the field.…”