Role of C‐C chemokine receptors 1 and 5 and CCL3/macrophage inflammatory protein‐1α in the cutaneous Arthus reaction: possible attenuation of their inhibitory effects by compensatory chemokine production

Abstract

The deposition of immune complexes induces an acute inflammatory response with tissue injury. Immune complex-induced tissue injury is mediated by inflammatory cell infiltration that is highly regulated by multiple chemokines. To assess the role of the chemokine receptors CCR1 and CCR5, and a ligand for these receptors CCL3/macrophage inflammatory protein1a, in this pathogenic process, the reverse passive cutaneous Arthus reaction was induced in mice lacking CCR1, CCR5, or CCL3. Edema was significantly attenuated in CCR1-deficient (CCR1 -/-) and CCL3 -/-mice but not CCR5 -/-mice, compared with wild-type mice. Numbers of infiltrating neutrophils and mast cells were reduced in CCL3 -/-and CCR1 -/-mice, respectively, compared with wild-type mice. CCR1 and CCR5 were expressed on neutrophils and mast cells. Remarkably, the intradermal mRNA expression of CCL5/RANTES, another ligand for CCR1 and CCR5, was increased in CCR5 -/-and CCL3 -/-mice, compared with wild-type mice, while the cutaneous CCL3 mRNA expression was augmented in CCR1 -/-and CCR5 -/-mice. These results indicate that CCR1, CCR5, and CCL3 cooperatively contribute to the cutaneous Arthus reaction, and also suggest that enhanced expression of CCL3 and CCL5 compensates for the loss of CCR1, CCR5, and CCL3 in the reaction.

CCR5 deficiency exacerbates T-cell-mediated hepatitis in mice

“…Finally, the unexpected finding of increased CCR5 ligand expression in CCR5 Ϫ/Ϫ mice has also been described in other disease models. 29,32,41 We also demonstrated that increased serum levels of CCR5 ligands in CCR5 Ϫ/Ϫ mice play a pathological role during Con A hepatitis, because their neutralization dramatically reduces the extent of hepatocellular damage in these mice. Interestingly, when each chemokine was neutralized individually with a monoclonal antibody, only CCL5 neutralization could protect against liver injury in CCR5 Ϫ/Ϫ mice.…”

Otitis Media and Nasopharyngeal Colonization inccl3−/−Mice

“…Other chemokines such as CCL2, CCL7, and CCL12 bind to different receptors but similarly recruit inflammatory cells, while cytokines such as macrophage migration inhibitory factor (MIF) can also be cooperatively involved in the trafficking of leukocytes (18,33). Support for the possibility of redundancy comes from studies demonstrating enhanced expression levels of alternative chemokines as a mechanism of compensation for a genetic loss of CCL3 in other systems (27,34). We evaluated the expression levels of CCL2, CCL7, and CCL12, regulated over the same time period as CCL3 during OM, in ccl3 Ϫ/Ϫ mice.…”

The pattern of immune cell infiltration in chromoblastomycosis: involvement of macrophage inflammatory protein-1 alpha/CCL3 and fungi persistence

“…Chemokines are classified into four subfamilies according to the configuration of cysteine residues near the N-terminal, depending on whether the first two cysteines are separated (CXC, CX3C) or not (CC, C) by an intervening amino acid [17][18] . Of these, MIP-1α (Macrophage inflammatory protein-1α, also designated CCL3) is a CC chemokine with potent chemotactic activity for various subsets of mononuclear leukocytes and also neutrophils 13,15,[17][18]25,27 , playing an important role in cellular responses in fungal diseases 14,16 . MIP-1α is a ligand of CCR1, which is found on Th1 cells, monocytes, macrophages 1,[20][21] and neutrophils 27 .…”

“…Of these, MIP-1α (Macrophage inflammatory protein-1α, also designated CCL3) is a CC chemokine with potent chemotactic activity for various subsets of mononuclear leukocytes and also neutrophils 13,15,[17][18]25,27 , playing an important role in cellular responses in fungal diseases 14,16 . MIP-1α is a ligand of CCR1, which is found on Th1 cells, monocytes, macrophages 1,[20][21] and neutrophils 27 . Conversely, CXCR3 is expressed preferentially on Th1 lymphocytes and at lower levels in Th2 cells, and its ligand comprises Mig, IP-10 and I-TAC 1,[20][21] .…”

“…In this setting, expression of selective recruitors of these cell types, such as chemokines, have not been previously assessed in CR. Chemokine and chemokine receptors are responsible for the leukocyte recruitment and activation in different inflammatory diseases 25,27 including fungal infections 23 . Chemokines are classified into four subfamilies according to the configuration of cysteine residues near the N-terminal, depending on whether the first two cysteines are separated (CXC, CX3C) or not (CC, C) by an intervening amino acid [17][18] .…”